Novel method and compounds

ABSTRACT

A method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, dementias such as Alzheimer&#39;s disease and manic depression which method comprises the administration of a pharmaceutically effective, non-toxic amount of a compound of formula (I):  
                 
 
     or a pharmaceutically acceptable derivative thereof, wherein:  
     R is hydrogen, alkyl, aryl, or aralkyl;  
     R 1  is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl;  
     R 2  is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl;  
     R 3  is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkyl wherein the aryl moiety is substituted or unsubstituted; or,  
     R 1  and R 3  together with the nitrogen to which they are attached form a single or fused, optionally substituted, saturated or unsaturated heterocylic ring;  
     to a human or non-human mammal in need thereof, and compounds of formula I.

[0001] This invention relates to a novel method for the treatment and/orprophylaxis of conditions associated with a need for inhibition ofglycogen synthase kinase-3 (GSK-3), especially diabetes, includingchronic neurodegenerative conditions, including dementias such asAlzheimer's disease, neurotraumatic diseases, such as acute stroke, mooddisorders such as schizophrenia and manic depression, and for thetreatment and/or prophylaxis of hair loss and cancer, and to certainnovel inhibitors of GSK-3 for use in such a method.

[0002] GSK-3 is a serine/threonine protein kinase composed of twoisoforms (α and β) which are encoded by distinct genes. GSK-3 is one ofseveral protein kinases which phosphorylates glycogen synthase (GS)(Embi et al Eur. J. Biochem. (107) 519-527 (1980)). The α and β isoformshave a monomeric structure of 49 and 47 kD respectively and are bothfound in mammalian cells. Both isoforms phosphorylate muscle glycogensynthase (Cross et al Biochemical Journal (303) 21-26 (1994)) and thesetwo isoforms show good homology between species (e.g. human and rabbitGSK-3α are 96% identical).

[0003] Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus,NIDDM) is a multifactorial disease. Hyperglycaemia is due to insulinresistance in the liver, muscle and other tissues coupled withinadequate or defective secretion of insulin from pancreatic islets.Skeletal muscle is the major site for insulin-stimulated glucose uptakeand in this tissue, glucose removed from the circulation is eithermetabolised through glycolysis and the TCA cycle, or stored as glycogen.Muscle glycogen deposition plays the more important role in glucosehomeostasis and Type II diabetic subjects have defective muscle glycogenstorage.

[0004] The stimulation of glycogen synthesis by insulin in skeletalmuscle results from the dephosphorylation and activation of glycogensynthase (Villar-Palasi C. and Larner J. Biochim. Biophys. Acta (39)171-173 (1960), Parker P J et al., Eur. J. Biochem. (130) 227-234(1983), and Cohen P. Biochem. Soc. Trans. (21) 555-567 (1993)). Thephosphorylation and dephosphorylation of GS are mediated by specifickinases and phosphatases. GSK-3 is responsible for phosphorylation anddeactivation of GS, while glycogen bound protein phosphatase 1 (PP1G)dephosphorylates and activates GS. Insulin both inactivates GSK-3 andactivates PP1G (Srivastava A K and Pandey S K Mol. and Cellular Biochem.(182) 135-141 (1998)).

[0005] Chen et al., Diabetes (43) 1234-1241 (1994) found that there wasno difference in the mRNA abundance of PP1G between patients with TypeII diabetes and control patients, suggesting that an increase in GSK-3activity might be important in Type II diabetes. It has also recentlybeen demonstrated that GSK-3 is overexpressed in Type II diabetic muscleand that an inverse correlation exists between skeletal muscle GSK-3αactivity and insulin action (Nikoulina et al Glycogen Synthase Kinase-3in Human Skeletal Muscle: Relationship To Insulin Resistance in Type IIDiabetes. Diabetes (47(1)) 0028 Page A7 (1998) (Oral presentation)).Overexpression of GSK-3β and constitutively active GSK-3β (S9A, S9E)mutants in HEK-293 cells resulted in supression of glycogen synthaseactivity (Eldar-Finkelman et al., PNAS (93) 10228-10233 (1996)) andoverexpression of GSK-3 in CHO cells, expressing both insulin receptorand insulin receptor substrate 1 (IRS-1), resulted in an impairment ofinsulin action (Eldar-Finkelman and Krebs PNAS (94) 9660-9664 (1997)).Recent evidence for the involvement of elevated GSK-3 activity and thedevelopment of insulin resistance and type II diabetes in adipose tissuehas emerged from studies undertaken in diabetes and obesity proneC57BL/6J mice (Eldar-Finkelman et al., Diabetes (48) 1662-1666 (1999)).

[0006] GSK-3 has been shown to phosphorylate other proteins in vitroincluding the eukaryotic initiation factor eIF-2B at Serine⁵⁴⁰ (Welsh etal., FEBS Letts (421) 125-130 (1998)). This phosphorylation results inan inhibition of eIF-2B activity and leads to a reduction in this keyregulatory step of translation. In disease states, such as diabetes,where there is elevated GSK-3 activity this could result in a reductionof translation and potentially contribute to the pathology of thedisease.

[0007] Several aspects of GSK-3 functions and regulation in addition tomodulation of glycogen synthase activity indicate that inhibitors ofthis enzyme may be effective in treatment of disorders of the centralnervous system. GSK-3 activity is subject to inhibitory phosphorylationby PI 3 kinase-mediated or Wnt-1 class-mediated signals that can bemimicked by treatment with lithium, a low mM inhibitor of GSK-3(Stambolic V., Ruel L. and Woodgett J. R. Curr. Biol. 1996 6(12):1664-8).

[0008] GSK-3 inhibitors may be of value as neuroprotectants in treatmentof acute stroke and other neurotraumatic injuries. Roles for PI 3-kinasesignalling through PKB/akt to promote neuronal cell survival are wellestablished, and GSK-3 is one of a number of PKB/akt substrates to beidentified that can contribute to the inhibition of apoptosis via thispathway (Pap & Cooper, (1998) J. Biol. Chem. 273: 19929-19932). Evidencesuggests that astrocytic glycogen can provide an alternative energysource to facilitate neuronal survival under conditions of glucosedeprivation (for example see Ransom, B. R. and Fern, R. (1997) Glia 21:134-141 and references therein). Lithium is known to protect cerebellargranule neurons from death (D'Mello et al., (1994) Exp. Cell Res. 211:332-338 and Volonte et al (1994) Neurosci. Letts. 172: 6-10) and chroniclithium treatment has demonstrable efficacy in the middle cerebralartery occlusion model of stroke in rodents (Nonaka and Chuang, (1998)Neuroreport 9(9): 2081-2084). Wnt-induced axonal spreading and branchingin neuronal culture models has been shown to correlate with GSK-3inhibition (Lucas & Salinas, (1997) Dev. Biol. 192: 31-44) suggestingadditional value of GSK-3 inhibitors in promoting neuronal regenerationfollowing neurotraumatic insult.

[0009] Tau and β-catenin, two known in vivo substrates of GSK-3, are ofdirect relevance in consideration of further aspects of the value ofGSK-3 inhibitors in relation to treatment of chronic neurodegenerativeconditions. Tau hyperphosphorylation is an early event inneurodegenerative conditions such as Alzheimer's disease (AD), and ispostulated to promote microtubule disassembly. Lithium has been reportedto reduce the phosphorylation of tau. enhance the binding of tau tomicrotubules, and promote microtubule assembly through direct andreversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D.C., Klein P. S. and Lee V. M. J.Biol. Chem. 1997 272(40) 25326-32).β-catenin is phosphorylated by GSK-3 as part of a tripartite complexwith axin, resulting in β-catenin being targetted for degradation (Ikedaet al., (1998) EMBO J. 17: 1371-1384). Inhibition of GSK-3 activity is akey mechanism by which cytosolic levels of catenin are stabilised andhence promote β-catenin-LEF-1/TCF transcriptional activity (Eastman,GrosschedI (1999) Curr. Opin. Cell Biol. 11: 233). Rapid onset ADmutations in presenilin-1 (PS-1) have been shown to decrease thecytosolic β-catenin pool in transgenic mice. Further evidence suggeststhat such a reduction in available β-catenin may increase neuronalsensitivity to amyloid mediated death through inhibition ofβ-catenin-LEF-1/TCF transcriptional regulation of neuroprotective genes(Zhang et al., (1998) Nature 395: 698-702). A likely mechanism issuggested by the finding that mutant PS-1 protein confers decreasedinactivation of GSK-3 compared with normal PS-1 (Weihl, C. C., Ghadge,G. D., Kennedy, S. G., Hay, N., Miller, R. J. and Roos, R. P.(1999) J.Neurosci. 19: 5360-5369).

[0010] WO 97/41854 (University of Pennsylvania) discloses that aneffective drug for the treatment of manic depression is lithium, butthat there are serious drawbacks associated with this treatment. Whilstthe precise mechanism of action of this drug for treatment of manicdepression remains to be fully defined, current models suggest thatinhibition of GSK-3 is a relevant target that contributes to themodulation of AP-1 DNA binding activity observed with this compound (seeManji et al., (1999) J. Clin. Psychiatry 60 (suppl 2): 27-39 forreview).

[0011] GSK-3 inhibitors may also be of value in treatment ofschizophrenia. Reduced levels of β-catenin have been reported inschizophrenic patients (Cotter D, Kerwin R, al-Sarraji S. Brion J P,Chadwich A. Lovestone S, Anderton B, Everall I. 1998 Neuroreport9:1379-1383 ) and defects in pre-pulse inhibition to startle responsehave been observed in schizophrenic patients (Swerdlow et al., (1994)Arch. Gen. Psychiat. 51: 139-154). Mice lacking the adaptor proteindishevelled-1, an essential mediator of Wnt-induced inhibition of GSK-3,exhibit both a behavioural disorder and defects in pre-pulse inhibitionto startle response (Lijam N, Pavlor R, McDonald M P, Crawley J N, DengC X, Herrup K, Stevens K E, Maccaferri G, McBain C J, Sussman D J,Wynshaw-Boris A. (1997) Cell 90: 895-905). Together, these findingsimplicate deregulation of GSK-3 activity as contributing toschizophrenia. Hence, small molecule inhibitors of GSK-3 catalyticactivity may be effective in treatment of this mood disorder.

[0012] The finding that transient β-catenin stabilisation may play arole in hair development (Gat et al., Cell (95) 605-614(1998)) suggeststhat GSK-3 inhibitors could be used in the treatment of baldness.

[0013] Certain substitued 3-amino-4-arylmaleimides are disclosed inTetrahedron (1998), 54(9), 1745-1752; Liebigs Annalen 1894, 282, 81; BE659639; J Amer Chem Soc 1958, 80, 1385; J. Prakt. Chem. (1979), 321(5),787-96; Eur. J. Org. Chem. (1998), (7), 1467-1470; Chem. Heterocycl.Compd. (N.Y.) (1997), 33(1), 69-73; J. Prakt. Chem. (1987), 329(4),587-91; Collect. Czech. Chem. Commun. (1985), 50(6), 1305-11;Tetrahedron (1984), 40(18), 3499-502; J. Prakt. Chem. (1983), 325(2),293-300; J Prakt Chem 1983, 325 (2) 293-300; Tetrahedron (1980), 36,1801-5; which compounds have no disclosed pharmaceutical utility.

[0014] Certain 3-amino-4-arylmaleimides are disclosed in Bioorg. Med.Chem. Lett. (1995), 5(1), 67-72; J. Med. Chem. (1992), 35(1), 177-84;Tetrahedron Lett. (1990), 31(36), 5201-4; EP 328026; Bioorg. Med. Chem.Lett. (1994), 4(24), 2845-50, which compounds are disclosed as beingprotein kinase C inhibitors or trypanothione reductase inhibitors.Certain 3-amino-4-arylmaleimides are disclosed in DE 4005969 and DE4005970 as having activity as anti-allergics and immunotherapeutics.

[0015] U.S. Pat. No. 3,335,147 discloses certain3-amino-4-arylmaleirnides as having topical anaesthetic activity. DE19744257 discloses certain 3-amino-4-arylmaleimides as being tyrosinekinase inhibitors. Chem. Pharm. Bull. (1998), 46(4), 707-710 disclosescertain 3-amino-4-arylmaleimides as being trypanothione reductaseinhibitors. SA 672268 discloses certain 3-amino-4-arylmaleimides asbeing antimicrobials.

[0016] None of the above mentioned references discloses that the3-amino-4-arylmaleimides possess GSK-3 inhibitor activity.

[0017] We have now discovered that a series of certain3-amino-4-arylmaleimides are particularly potent and selectiveinhibitors of GSK-3. These compounds are indicated to be useful for thetreatment and/or prophylaxis of conditions associated with a need forinhibition of GSK-3, such as diabetes, chronic neurodegenerativeconditions, including dementias such as Alzheimer's disease, manicdepression, mood disorders, such as schizophrenia, neurotraumaticdiseases, such as acute stroke, hair loss, and cancer. Certain of thesecompounds are novel and such compounds comprise a further aspect of theinvention. In addition, as indicated above it is considered that GSK-3inhibitors per se are potentially useful in the treatment and/orprophylaxis of mood disorders, such as schizophrenia, neurotraumaticdiseases, such as acute stroke, and for the treatment and/or prophylaxisof cancer and hair loss.

[0018] Accordingly, in a first aspect, the present invention provides amethod for the treatment of conditions associated with a need forinhibition of GSK-3, such as diabetes, dementias such as Alzheimer'sdisease and manic depression which method comprises the administrationof a pharmaceutically effective, non-toxic amount of a compound offormula (I):

[0019] or a pharmaceutically acceptable derivative thereof, wherein:

[0020] R is hydrogen, alkyl, aryl, or aralkyl;

[0021] R¹ is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl;

[0022] R² is substituted or unsubstituted aryl or substituted orunsubstituted heterocyclyl;

[0023] R³ is hydrogen, substituted or unsubstituted alkyl, cycloalkyl,alkoxyalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl or aralkyl wherein the aryl moiety issubstituted or unsubstituted; or,

[0024] R¹ and R³ together with the nitrogen to which they are attachedform a single or fused, optionally substituted, saturated or unsaturatedheterocylic ring;

[0025] to a human or non-human mammal in need thereof

[0026] Suitably, R is hydrogen, C₁₋₆alkyl, such as methyl or ethyl, or Ris phenyl or benzyl.

[0027] Preferably, R is hydrogen.

[0028] Suitably. R¹ is hydrogen, C₁₋₆alkyl, such as methyl, ethyl, or R¹is hydroxyethyl or methoxyethyl.

[0029] Preferably, R¹ is hydrogen.

[0030] When R² is substituted or unsubstituted aryl, examples of arylgroups include phenyl and naphthyl.

[0031] When R² is substituted or unsubstituted heterocyclyl, examples ofheterocyclyl groups include indolyl, benzofiuranyl, thienyl andbenzothienyl.

[0032] When R² is substituted phenyl, suitable substituents include upto three groups independently selected from halo, C₁₋₆alkoxy, nitro,perfluoroC₁₋₆alkyl, benzoyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylsulphonyl,hydroxy, —O(CH₂)_(w)O— where w is 1 to 4, phenoxy, benzyloxy,C₁₋₆alkoxyC₁₋₆alkyl, perfluoroC₁₋₆alkoxy, C₁₋₆aylkS—,perfluoroC₁₋₆alkylS—, (diC₁₋₆alkyl)N—, amino, C₁₋₆alkylcarbonylamino,substituted or unsubstituted ureido, phenylcarbonylamino,benzylcarbonylamino, styrylcarbonylamino, (diC₁₋₆alkoxy)(phenyl)C—,C₁₋₆alkyl, and phenyl.

[0033] Suitable substituents for ureido include fluorophenyl,phenylC₁₋₆alkyl-, cyclohexyl, C₁₋₆alkenyl, C₁₋₆alkyl, andC₁₋₆alkoxyphenyl.

[0034] When R² is substituted indolyl, suitable substituents includeC₁₋₆alkyl.

[0035] When R² is substituted benzothienyl, suitable substituentsinclude C₁₋₆alkyl.

[0036] Suitably, R² is substituted or unsubstituted phenyl.

[0037] Favourably, R² is phenyl substituted with;

[0038] 4-Cl; 3-Cl; 2-Cl; 2,4-di-Cl; 3,4-di-Cl; 3,5-di-Cl; 2,6-di-Cl;2-F-6-Cl; 2-F; 3-F; 4-F; 2,3-di-F; 2,5-di-F; 2,6-di-F; 3,4-di-F;3,5-di-F; 2,3,5-tri-F; 3,4,5-tri-F; 2-Br; 3-Br; 4-Br; 2-I; 4-I;3-Cl-4-OMe: 3-NO₂-4-Cl; 2-OMe-5-Br; 2-NO₂; 3-NO₂; 4-NO₂; 2-CF₃; 3-CF₃;4-CF₃; 3,5-di-CF₃; 4-PhC(O)—; 4-MeO(O)C—; 4-MeSO₂—; 4-OH; 2-OMe; 3-OMe;4-OMe; 2,4-di-OMe; 2,5-di-OMe; 3,4-di-OMe; 3,4-OCH₂O—; 3,4,5-tri-OMe;3-NO-₂-4-OMe; 4-OnBu; 2-OEt; 2-OPh; 3-OPh; 4-OPh; 2-OCH₂Ph; 4-OCH₂Ph;4-(MeOCH₂); 2-OCF₃; 4-OCF₃; 4-SMe; 3-SCF₃; 4-NMe₂; 3-NH₂; 3-(NHC(O)Me);3-[NHC(O)NH(3-F-Ph)]; 3-[NHC(O)NH(CH₂)₂Ph]; 3-[NHC(O)NHCyclohexyl];3-[NHC(O)NHCH₂CH═CH₂]; 3-[NHC(O)Ph]; 3-[NHC(O)CH₂Ph];3-[trans-NHC(O)CH═CHPh]; 3-[NHC(O)nPr]; 3-[NHC(O)NHEt];3-[NHC(O)NH(3-OMe-Ph)]; 4-[C(OMe)₂Ph]; 2-Me; 3-Me; 4-Me; 4-iPr;2,5-di-Me; 3,5-di-Me, 4-Ph, 2,3-[(—CH₂═CH₂—)], or 3,4-[(—CH₂═CH₂—)].

[0039] When R³ is alkyl, examples include methyl and ethyl.

[0040] When R³ is cycloalkyl, examples include cyclohexyl.

[0041] When R³ is alkoxyalkyl, examples include methoxyethyl.

[0042] When R³ is aralkyl, examples include benzyl and phenylethyl.

[0043] When R³ is substituted or unsubstituted aryl, examples includefluorenyl, phenyl, and dibenzofuryl.

[0044] When R³ is substituted or unsubstituted heterocyclyl, examplesinclude thienyl, oxazolyl, benzoxazolyl, pyridyl, and pyrimidinyl.

[0045] When R¹ and R³ together with the nitrogen atom to which they areattached form a fused heterocyclic ring, which ring may be unsubstitutedor substituted, examples include indolinyl, indolyl, oxindolyl,benzoxazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,benzimidazolyl, benzazepinyl, isoindolin-2-yl, and1,3,3-trimethyl-6-azabicyclo[3,2,1 ]oct-6-yl.

[0046] When R¹ and R³ together with the nitrogen atom to which they areattached form a single heterocyclic ring, which ring may beunsubstituted or substituted, examples include1-phenyl-1,3,8-triazaspiro-[4,5]-decan-4-one-8-yl, piperazinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and apyridinium ring.

[0047] When R³ is substituted phenyl, suitable substituents include upto three groups independently selected from substituted or unsubstitutedC₁₋₆alkyl, phenyl, benzyl, substituted or unsubstituted C₁₋₆alkylS—,halo, hydroxy, substituted or unsubstituted C₁₋₆alkoxy, substituted orunsubstituted phenoxy, indolyl, naphthyl, carboxy, C₁₋₆alkoxycarbonyl,benzyloxy, pentafluorophenoxy, nitro, N-substituted or unsubstitutedcarbamoyl, substituted or unsubstituted C₁₋₆alkylcarbonyl, benzoyl,cyano, perfluoroC₁₋₆alkylSO2—, C₁₋₆alkylNHSO₂—, oxazolyl,C₁₋₆alkylcarbonylpiperazinyl, substituted or unsubstituted phenylS—,C₁₋₆alkylpiperazinyl-, cyclohexyl, adamantyl, trityl, substituted orunsubstituted C₁₋₆alkenyl, perfluoroC₁₋₆alkyl, perfluoroC₁₋₆alkoxy,perfluoroC₁₋₆alkylS—, aminosulphonyl, alkylaminosulphonyl,dialkylaminosulphonyl, arylaminosulphonyl, morpholino,(diC₁₋₆alkyl)amino, C₁₋₆alkylCONH—,(diC₁₋₆alkoxy)phenyl(CH₂)_(n)NHC(O)CH(phenyl)S— where n is 1 to 6, andC₁₋₆alkylCON(C₁₋₆alkyl)-, thiazolidinedionylC₁₋₆alkyl, phenylCH(OH)—,substituted or unsubstituted piperazinylC₁₋₆alkoxy, substituted orunsubstituted benzoylamino; or —[CH═CH—C(O)O]—, —[(CH═CH)₂]—,—[(CH₂)_(x)N(C₁₋₆alkylcarbonyl)]-, —(CH₂)_(x)—, —SCH═N—,—SC(C₁₋₆alkyl)═N—, —OCF₂O—, —CH═N—NH—, —CH═CH—NH—, —OC(NHC₁₋₆alkyl)═N—,—OC(O)NH—, —C(O)NC₁₋₆alkylC(O)—, —[CH═CH—CH═N]—,—[CH═C(C₁₋₆alkylcarbonyl)O]—, —C(O)NHC(O)—, —[(CH₂)_(x)C(O)]—, —N═N—NH—,—N═C(C₁₋₆alkyl)O—, —O(CH₂)_(x)O—, —(CH₂)_(x)SO₂(CH₂)_(y)—,—N(C₁₋₆alkylcarbonyl)(CH₂)_(x)— where x and y are independently 1 to 4,pyrimidin-2-yloxy, phenylamino, N-[pyrimidin-2-yl]-N-[C₁₋₆alkyl]amino,C₁₋₆alkylsulphonylamino, and 1,2,3-thiadiazolyl.

[0048] Suitable substituents for C₁₋₆alkyl include hydroxy, carboxy,unsubstituted or N-substituted carbamoyl, N-morpholinylcarbonyl,C₁₋₆alkylaminocarbonyl, fluoro, cyano, C₁₋₆alkyl,C₁₋₆alkoxycarbonylamino, amino, C₁₋₆alkylcarbonylamino, benzoylamino,phenylaminocarbonylamino, C₁₋₆alkoxycarbonyl, phosphono, mono- orbisC₁₋₆alkylphosphonate, C₁₋₆alkylaminosulphonyl, andC₁₋₆alkylcarbonylaminoC₁₋₆alkylaminoCO—,

[0049] Suitable substituents for C₁₋₆alkylS— include carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl, unsubstituted orN-substituted carbarnoyl, and fluoro.

[0050] Suitable substituents for C₁₋₆alkoxy include C₁₋₆alkoxy, phenyl,carboxy, C₁₋₆alkoxycarbonyl, unsubstituted or N-substituted carbamoyl,and phenyl.

[0051] Suitable substituents for carbamoyl include C₁₋₆alkyl, andC₁₋₆alkoxyC₁₋₆alkyl.

[0052] Suitable substituents for C₁₋₆alkylcarbonyl include carboxy, andC₁₋₆alkoxycarbonyl.

[0053] Suitable substituents for phenylS— include chloro, nitro,carboxy, C₁₋₆alkylaminocarbonyl, unsubstituted or N-substitutedcarbamoyl, and C₁₋₆alkoxycarbonyl.

[0054] Suitable substituents for C₁₋₆alkenyl include(diC₁₋₆alkyl)aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, carbarnoyl, andphenyl.

[0055] Suitable substituents for piperazinylC₁₋₆alkoxy include methyl.

[0056] Suitable substituents for phenoxy include chloro.

[0057] Suitable substituents for benzoylamino include hydroxy.

[0058] When R³ is substituted benzofuryl, suitable substituents includeC₁₋₆alkylcarbonyl.

[0059] When R³ is substituted thienyl, suitable substituents includeC₁₋₆alkylcarbonyl.

[0060] When R³ is substituted oxazolyl, suitable substituents includeC₁₋₆alkyl.

[0061] When R³ is substituted benzoxazolyl, suitable substituentsinclude halo.

[0062] When R³ is substituted pyridyl, suitable substituents include upto three substituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,and halo.

[0063] Suitably, R³ is substituted or unsubstituted phenyl.

[0064] Favourably, R³ is phenyl substituted with;

[0065] 2-Me; 2-Et; 2-iPr; 2-CH₂OH; 2-Ph; 2-CH₂Ph; 2-SMe; 2-F; 2-Cl;2-OH; 2-OMe; 2-OPh; 2-Me-5-F; 2-Me-3-Cl; 2-Me-4-Cl; 2-Me-5-Cl;2-Me-3-Br; 2,3-di-Me; 2,4-di-Me; 2-Me-4-OH; 2-Me-4-OMe; 2-Me-5-CH₂OH;2,4,6-tri-Me; 2-(2-Indolyl); (1-Naphthyl); 2-Me-5-COOH; 2-Me-5-COOMe;2-OH-5-COOH; 2-[O(CH₂)₂OMe]-5-[(CH₂)₂COOH];2-[SCH(Ph)CONH(CH₂)₂(3,4-di-OMePh)]; 3-Me; 3-Et; 3-CH₂OH; 3-CH₂OH-6-Me;3-CH₂OH-4-OMe; 3-(CH₂NMe₂)-4-OMe; 3-[CH₂COOH]; 3-[CH₂COOMe];3-[CH₂CONH₂]; 3-[CH₂CONHMe]; 3-[CH₂-(thiazolidine-2,4-dion-5-yl)];3-SMe; 3-F; 3-Cl; 3-Br; 3-I; 3-CF₃; 3-OH; 3-OMe; 3-OCH₂Ph; 3-OiPr;3-OPh; 3-O-pentafluorophenyl; 3-(OCH₂CO₂H); 3-(OCH₂CO₂Me);3-(OCH₂CO₂Et); 3-NO₂; 3-CO₂H; 3-CO₂Me; 3-CONH₂; 3-CONHMe;3-CONHCH₂CH₂OMe; 3-COMe; 3-COPh; 3-(COCH₂CH₂CO₂H); 3-(COCH₂CH₂CO₂Me);3-CN; 3-SO₂CF3; 3-SO₂NH-nBu; 3-(5-oxazolyl);3-[4-methylpiperazin-1-yl]-4-OMe; 3-[O-(pyrimidin-2-yl)]; 3-OH-4-OMe;3,4-di-OMe; 3,5-di-OMe; 3,4-di-Me; 3,5-di-Me;3-[trans-CH═CHCONMe₂]-4-Cl; 3-F-4-Me; 3-Cl-4-Me; 3-Br-4-Me; 3,5-di-F;3,4-di-Cl; 3,5-di-Cl; 3,5-di-Br; 3-Cl-4-Br; 3-Cl-4-I; 3-Cl-4-OH;3-Br-4-OH; 3-F-4-OMe; 3-Cl-4-OMe; 3-Cl-4-SMe; 3-Br-4-Cl; 3-Br-4-OCF₃;3-Br-5-CF₃; 3,5-di-Cl-4-OH; 3,5-di-Br-4-OH; 3,5-di-Cl-4-Me;3,5-di-Br-4-Me; 3-[CH₂CH(Me)CO₂H]; 3-CO₂H-4-Cl; 3-CO₂Me-4-Cl;3-CO₂H-4-OH; 3-CONH₂-4-Me; 3-NO₂-4-OH; 3-CO₂H-4-SPh;3-CO₂H-4-[S-(2-CO₂H-Ph)]; 3-CO₂H-4-[S-(2-CONHMe-Ph)];3-CO₂Et-4-[S-(2-CO₂Et-Ph)]; 3-CO₂H-4-[S-(3-CO₂H-Ph)];3-CO₂Me-4-[S-(4-Cl-Ph)]; 4-[N(Me)(Pyrimidin-2-yl)]; 4-Me; 4-nBu; 4-tBu;4-Cyclohexyl; 4-Adamantyl; 4-CPh₃; 4-CH₂CN; 4-CH(OH)Me; 4-CH(OMe)Me;4-CH₂OH; 4-CH₂NHC(O)t-Bu; 4-CH₂NH₂; 4-CH₂NHCOMe; 4-CH₂NHCOPh;4-CH₂NHCONHPh; 4-CH₂CO₂H; 4-CH₂CO₂Me; 4-[CH₂P(O)(OH)₂];4-[CH₂P(O)(OEt)₂]; 4-[CH₂SO₂NHMe]; 4-(CH₂)₂OH; 4-(CH₂)₂NH₂;4-(CH₂)₂NHCOPh; 4-(CH₂)₂NHC(O)Ot-Bu; 4-[(CH₂)₂CO₂H]; 4-[(CH₂)₂CO₂Me];4-(CH₂CH₂CONH₂); 4-[CH₂CH₂CONH(CH₂)₆NHCOMe]; 4-[(CH₂)₃CO₂H];4-[(CH₂)₃CO₂Me]; 4-[CH═CH₂]; 4-(CH═CHCO₂H); 4-(CH═CHCO₂Et);4-(CH═CHCONH₂); 4-(CH═CHPh); 4-(CH═CH(4-OHPh));4-[1,2,3-thiadiazol-4-yl]; 4-[OCH₂-(1-methyl-piperazin-4-yl)];4-[4-methylpiperazin-1-yl]; 4-CF₃; 4-SMe; 4-(SCH₂CO₂H); 4-(SCH₂CO₂Me);4-[SCH₂CONH(CH₂)₂OMe]; 4-SCF₃; 4-[S-(4-NO₂-Ph)]; 4-[S-(2-CO₂H-Ph)];4-[S-(3-CO₂H-Ph)]; 4-SO₂NH₂; 4-F; 4-Cl; 4-Br; 4-I; 4-OH; 4-OMe; 4-OnBu;4-OPh; 4-[O-(4-Cl-Ph)]; 4-OCH₂Ph; 4-OCH₂CO₂Me; 4-COPh; 4-COMe; 4-CONH₂;4-CO₂H; 4-CN; 4-NO₂; 4-morpholinyl; 4-[CH₂CO-morpholin-1-yl)];4-[CH₂CONH(CH₂)₂OMe]; 4-[(CH₂)₂CONH(CH₂)₆NHC(O)Ot-Bu];4-[(CH₂)₂CONH(CH₂)₆NH₂]; 4-[(CH₂)₂CONH(CH₂)₆NH-biotinyl]; 4-NMe₂;4-NHCOMe; 4-N(Me)COMe, 2,3-di-F; 4-[NHCO(Ph-2-OH)], 4-(phenylamino);4-methylsulphonylamino, 2,4-di-F; 2,5-di-F; 2-OMe-3-F; 3-CH₂OMe;3-CH(OH)Ph; 3,4,-di-F; 3-CO₂H-4-CH₂CO₂H; 3-CO₂H-4-[S-(2-CO₂Et)Ph];3-CO₂Et-4-[S-(4-CO₂H)Ph]; 3-CONHMe4-[S-(2-CONHMe)-Ph];3-[4-(dichloroacetyl)piperazin-1-yl]-4-OMe; 4-CH₂CONH₂; 4-SPh;4-[S-(4-CO₂H-Ph)]; and 4-OCH₂CO₂H.

[0066] When R¹ and R³ together with the nitrogen atom to which they areattached form indolinyl, suitable substituents include C₁₋₆alkyl,perfluoroC₁₋₆alkyl, C₁₋₆alkylSO₂NH-hydroxyC₁₋₆alkyl, carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxy, halo, t-butoxycarbonylpiperazin-1-yl,4-(C₁₋₆alkyl)piperazinyl, piperazinyl, amido, and nitro.

[0067] When R¹ and R³ together with the nitrogen atom to which they areattached form piperazinyl, suitable substituents include alkylcarbonyl,alkyl, or aryl.

[0068] When R¹ and R³ together with the nitrogen atom to which they areattached form tetrahydroquinolinyl, suitable substituents includeperfluoroC₁₋₆alkyl.

[0069] When R¹ and R³ together with the nitrogen atom to which they areattached form a pyridinium ring, suitable substituents include amino.

[0070] When R¹ and R³ together with the nitrogen atom to which they areattached form pyrrolidinyl, suitable substituents include hydroxy.

[0071] When R¹ and R³ together with the nitrogen atom to which they areattached form piperidinyl, suitable substituents include benzyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyl, hydroxy, carbamoyl, and C₁₋₆alkoxycarbonyl.

[0072] When R¹ and R³ together with the nitrogen atom to which they areattached form oxindolyl, suitable substituents include C₁₋₆alkyl.

[0073] There is a sub-group of compounds, falling wholly within formula(I), and being of formula (IA), wherein R, R¹, R² and R³ are as definedin relation to formula (I), with the proviso that formula (IA) does notinclude the following compounds, hereinafter referred to as List A:

[0074] 3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;

[0075]3-[4-(diphenylmethyl)-1-piperazinyl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0076] 3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;

[0077] 1-methyl-3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;

[0078] 1-ethyl-3-phenyl-4-(4-chorophenylpiperazino)-pyrrole-2,5-dione;

[0079] 1-allyl-3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;

[0080] 3-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;

[0081]1-(1-methyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)pyridiniumchloride;

[0082]1-[1-(4-methyl-pentyl)-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl]pyridiniumchloride;

[0083]1-(1-dodecyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0084]3-[2-benzo[b]thien-2-yl-3-[4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]-carbamimidothioicacid, propyl ester;

[0085]3-(dimethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0086] 3-(1H-indol-3-yl)-1-methyl-4-(phenylamino)-1H-pyrrole-2,5-dione;

[0087]3-(1H-indol-3-yl)-1-methyl-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrole-2,5-dione;

[0088] 3-(1H-indol-3-yl)-1-methyl-4-(methylamino)-1H-pyrrole-2,5-dione;

[0089]3-(1H-imidazo[4,5-b]pyridin-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0090]3-(6-chloro-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0091]3-(6-amino-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0092]3-(1H-indol-3-yl)-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione;

[0093]3-(1-H-indol-3-yl)-1-methyl-4-(1-piperidinyl)-1H-pyrrole-2,5-dione;

[0094]1-acetyl-3-[2,5-dihydro-1-methyl-2,5-dioxo-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrol-3-yl]-1H-indole;

[0095]3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0096]3-(1H-benzotriazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0097]3-(1H-imidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0098]3-(1H-indol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0099]3-(1H-indazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0100]3-[3-[(dimethylamino)methyl]-1H-indol-1-yl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0101] 3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0102]3-(1H-indol-1-yl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0103] 3-amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0104] 3-amino-4-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0105] 1H-Indole-1-carboxylic acid,3-(4-amino-2,5-dihydro-1-methyl-2,5-dioxo-1H-pyrrol-3-yl)-,1,1-dimethylethyl ester;

[0106]3-(1H-indol-3-yl)-1-methyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;

[0107] Glycine,N-[2,5-dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl- ,ethyl ester;

[0108] 3-amino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0109]3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0110][[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0111]3-(1H-indol-3-yl)-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;

[0112]1-[3-[(3-aminopropyl)amino]propyl]-3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0113]1-[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]-3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0114]3-(1H-indol-3-yl)-1-[3-(4-methyl-1-piperazinyl)propyl]-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;

[0115]3,3′-[iminobis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0116]3,3′-[1,4-piperazinediylbis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0117] 3-[(5-aminopentyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0118]3-[[5-[(2-aminoethyl)amino]pentyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0119] 3-[(2-aminoethyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0120] 3-[(6-aminohexyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0121] 3-[(7-aminoheptyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0122]3-[[2-[(2-aminoethyl)amino]ethyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0123] Benzenepropanamide,.alpha.-amino-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl-, (S)—;

[0124] Pentanoic acid,4-amino-5-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]-5-oxo-, (S)—;

[0125] Pentanamide,2-amino-5-[(aminoiminomethyl)amino]-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl-, (S)—;

[0126] Benzenepropanamide,.alpha.-amino-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3)-yl]amino]pentyl]amino]ethyl-, (S)—;

[0127] Butanamide,4-[(aminoiminomethyl)amino]-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl-, (S)—;

[0128] 3-phenyl-4-(diethylamino)-pyrrole-2,5-dione;

[0129] 3-phenyl-4-(benzylamino)-pyrrole-2,5-dione;

[0130] 1-methyl-3-phenyl-4-(2-diethylaminoethylamino)-pyrrole-2,5-dione;

[0131] 1-allyl-3-phenyl-4-(2-dimethylaminoethylamino)-pyrrole-2,5-dione;and;

[0132] 1,3-diphenyl-4-piperidino-pyrrole-2,5-dione.

[0133] There is a further sub-group of compounds, falling wholly withinformula (I), and being of formula (IB), wherein R, R¹, R² and R³ are asdefined in relation to formula (I), with the proviso that formula (IB)does not include the following compounds, hereinafter referred to asList B:

[0134] 3-(4-methylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;

[0135] 3-(4-ethylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;

[0136] 3-(4-chlorophenyl)-4-(4-methyl-piperazin-1-yl)-pyrrole-2,5-dione;

[0137]3-[4-(diphenylmethyl)-1-piperazinyl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0138] 3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;

[0139] 3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;

[0140] 1-methyl-3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;

[0141] 1-ethyl-3-phenyl-4-(4-chlorophenylpiperazino)-pyrrole-2,5-dione;

[0142] 1-allyl-3 )-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;

[0143] 3-phenylamino-4-phenyl-1H-pyrrole-2,5-dione;

[0144] 3-phenyl-4-piperidin-1-yl-pyrrole-2,5-dione;

[0145]3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-pyrrole-2,5-dione;

[0146] 3-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;

[0147]1-(1-methyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0148]1-1-(4-methyl-pentyl)-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0149]1-(1-dodecyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0150]3-[2,5-dihydro-4-(1H-imidazol-1-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-1H-indole-1-carboxylicacid, 1,1-dimethylethyl ester;

[0151]3-[2-benzo[b]thien-2-yl-3-[4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]-carbamimidothioicacid, propyl ester;

[0152]3-(dimethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0153] 3-(1H-indol-3-yl)-1-methyl-4-(phenylamino)-1H-pyrrole-2,5-dione;

[0154]3-(1H-indol-3-yl)-1-methyl-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrole-2,5-dione;

[0155] 3-(1H-indol-3-yl)-1-methyl-4-(methylamino)-1H-pyrrole-2,5-dione;

[0156]3-(1H-imidazo[4,5-b]pyridin-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0157]3-(6-chloro-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0158]3-(6-amino-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0159]3-(1H-indol-3-yl)-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione;

[0160]3-(1H-indol-3-yl)-1-methyl-4-(1-piperidinyl)-1H-pyrrole-2,5-dione;

[0161]1-acetyl-3-[2,5-dihydro-1-methyl-2,5-dioxo-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrol-3-yl]-1H-indole;

[0162]3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0163]3-(1H-benzotriazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0164]3-(1H-imidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0165]3-(1H-indol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0166]3-(1H-indazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0167]3-[3-[(dimethylamino)methyl]-1H-indol-1-yl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0168] 3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0169]3-(1H-indol-1-yl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0170]3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione;

[0171] 3-amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0172] 3-amino-4-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0173] 1H-Indole-1-carboxylic acid,3-(4-amino-2,5-dihydro-1-methyl-2,5-dioxo-1H-pyrrol-3-yl)-,1,1-dimethylethyl ester;

[0174]3-(1H-indol-3-yl)-1-methyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;

[0175] Glycine,N-[2,5-dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl- ,ethyl ester;

[0176] 3-amino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0177]1-(4-methylphenyl)-3-[(4-methylphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;

[0178]3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0179]3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0180]3-(1H-indol-3-yl)-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;

[0181]1-[3-[(1-aminopropyl)amino]propy]-3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0182]1-[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]-3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0183] 3-(1H-indol-3-yl)-1-[3-(4-methyl-1-piperazinyl)propyl]-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;

[0184]3,3′-[iminobis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0185]3,3′-[1,4-piperazinediylbis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0186] 3-amino-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione;

[0187] 3-[(5-aminopentyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0188]3-[[5-[(2-aminoethyl)amino]pentyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0189] 3-[(2-aminoethyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0190] 3-[(6-aminohexyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0191] 3-[(7-aminoheptyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione:

[0192]3-[[2-[(2-aminoethyl)amino]ethyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0193] Benzenepropanamide,.alpha.-amino-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl-, (S)—;

[0194] Pentanoic acid,4-amino-5-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]-5-oxo-, (S)—;

[0195] Pentanamide,2-amino-5-[(aminoiminomethyl)amino]-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl-, (S)—;

[0196] Benzenepropanamide,.alpha.-amino-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl-, (S)—;

[0197] Butanamide,4-[(aminoiminomethyl)amino]-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl-, (S)—;

[0198] 3-(4-methylphenyl)-1-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione;

[0199]1,3-bis(4-methylphenyl)-4-[(4-methylphenyl)amino]-1H-pyrrole-2,5-dione;p

[0200] 3-amino-1,4-diphenyl-1H-pyrrole-2,5-dione;

[0201]3-(4-methylphenyl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione;

[0202]3-(4-methylphenyl)-1-phenyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;

[0203] 3-amino-4-(4-methylphenyl)-1-phenyl-1H-pyrrole-2,5-dione;

[0204]3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione;

[0205] 3-(4-nitrophenyl)-1-phenyl-4-phenylamino-1H-pyrrole-2,5-dione;

[0206] 3-amino-1-methyl-4-p-tolyl-1H-pyrrole-2,5-dione;

[0207] 3-(2-diethylamino-ethylamino)-4-phenyl-pyrrole-2,5-dione;

[0208]3-[butyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;

[0209]3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;

[0210]3-[benzyl-(2-dimethylamino-ethyl)-amino]-1-methyl-4-phenyl-pyrrole-2,5-dione;

[0211]3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-(4-chloro-phenyl)-pyrrole-2,5-dione;

[0212]3-[benzyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;

[0213]3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-(3-methoxy-phenyl)-pyrrole-2,5-dione;

[0214]3-(4-chloro-phenyl)-4-[2-(4-methyl-piperazin-1-yl)-ethylamino]-pyrrole-2,5-dione;

[0215]3-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-phenyl-pyrrole-2,5-dione;

[0216] 3-phenyl-4-(diethylamino)-pyrrole-2,5-dione;

[0217] 3-phenyl-4-(benzylamino)-pyrrole-2,5-dione;

[0218] 1-methyl-3-phenyl-4-(2-diethylaminoethylamino)-pyrrole-2,5-dione;

[0219] 1-allyl-3-phenyl-4-(2-dimethylaminoethylamino)-pyrrole-2,5-dione;and;

[0220] 1,3-diphenyl-4-piperidino-pyrrole-2,5-dione.

[0221] It is considered that the compounds of formula (IB) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IB) or a derivative thereof.

[0222] There is a subgroup of compounds falling wholly within formula(I) of formula (IC):

[0223] wherein;

[0224] R and R¹ are as defined in relation to formula (I);

[0225] R¹⁰ represents hydrogen or one or more substituents, suitably upto three, selected from the list consisting of: alkoxycarbonyl,alkoxyalkyl, perfluoroalkyl, perfluoroalkylS—, perfluoroalkylO—,phenyl(di-C₁₋₆alkoxy)C—, benzoyl, C₁₋₆alkylSO₂—, —[(CH═CH)₂]—, phenyl,nitro, —OCH₂O—, benzyloxy, phenoxy, halo, hydroxy, alkyl, alkoxy, amino,mono- or di-alkyl amino or thioalkyl;

[0226] R¹¹ represents hydrogen or one or more substituents, suitably upto three, selected from the list consisting of: substituted orunsubstituted C₁₋₆alkyl, phenyl, benzyl, substituted or unsubstitutedC₁₋₆alkylS—, halo, hydroxy, substituted or unsubstituted C₁₋₆alkoxy,substituted or unsubstituted phenoxy, indolyl, naphthyl, carboxy,C₁₋₆alkoxycarbonyl, benzyloxy, phenoxy, pentafluorophenoxy, nitro,substituted or unsubstituted carbamoyl, substituted or unsubstitutedC₁₋₆alkylcarbonyl, benzoyl, cyano, perfluoroC₁₋₆alkylSO₂—,C₁₋₆alkylNHSO₂—, oxazolyl, substituted or unsubstituted phenylS—,C₁₋₆alkylpiperazinyl-, C₁₋₆alkylcarbonylpiperazinyl-,1,2,3-thiadiazolyl, pyrimidin-2-yloxy, N-[pyrimidin-2-yl]-N-methylamino,phenylamino, C₁₋₆alkylsulphonylamino, N-morpholinylcarbonyl, cyclohexyl,adamantyl, trityl, substituted or unsubstituted C₁₋₆alkenyl,perfluoroC₁₋₆alkyl, perfluoroC₁₋₆alkoxy, perfluoroC₁₋₆alkylS—,aminosulphonyl, morpholino, (diC₁₋₆alkyl)amino, C₁₋₆alkylCONH—,(diC₁₋₆alkoxy)phenyl(CH₂)_(n)NHC(O)CH(phenyl)S— where n is 1 to 6, andC₁₋₆alkylCON(C₁₋₆alkyl)-, thiazolidinedionylC₁₋₆alkyl, phenylCH(OH)—,substituted or unsubstituted piperazinylC₁₋₆alkoxy, substituted orunsubstituted benzoylamino;

[0227] or —(CH₂)_(x)—, —SCH═N—, —SC(C₁₋₆alkyl)═N—, —OCF₂O—,—[CH═CHC(O)O]—, —[N═CH—CH═CH]—, —CH═N—NH—, —CH═CH—NH—,—OC(NHC₁₋₆alkyl)═N—, —OC(O)NH—, —C(O)NMeC(O)—, —C(O)NHC(O)—,—(CH₂)_(x)C(O)—, —N═N—NH—, —N═C(C₁₋₆alkyl)O—, —O(CH₂)_(x)O—,—(CH₂)_(x)SO₂(CH₂)_(y)—,

[0228] and —N(C₁₋₆alkylcarbonyl)(CH₂)_(x)—, where x and y areindependently 1 to 4.

[0229] There is a subgroup of compounds within formula (IC) of formula(IC′) wherein R, R¹, R¹⁰ and R¹¹ are as defined in relation to formula(IC) with the proviso that formula (IC′) does not include:

[0230] 3-phenylamino-4-phenyl-1H-pyrrole-2,5-dione;

[0231]1-(4-methylphenyl)-3-[(4-methylphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;

[0232] 3-(4-methylphenyl)-1-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione;

[0233]1,3-bis(4-methylphenyl)-4-[(4-methylphenyl)amino]-1H-yrrole-2,5-dione,or;

[0234] 3-(4-nitrophenyl)-1-phenyl-4-phenylamino-1H-pyrrole-2,5-dione.

[0235] Suitably, R is hydrogen.

[0236] Suitably, R¹ is hydrogen.

[0237] Suitably, R¹⁰ represents hydrogen or one or more substituentsselected from the list consisting of: halo, hydroxy, alkyl, alkylthio,alkoxy, amino or methylenedioxy, especially one or more halo and alkylgroups.

[0238] Favourably, R¹⁰ represents hydrogen or the substituents selectedfrom the list consisting of: 2-Br, 2-Cl, 2-F, 2-OMe, 3-Cl, 3-F, 3-Me,3-NH₂, 3-OMe, 4-Br, 4-Cl, 4-I, 4-Me, 4-OH, 4-OMe, 4-SMe, 2,3-di-F,2,5-di-F, 2,6-di-F, 3,4-di-F, 3,5-di-F, 2,3,5-tri-F, 2,4-di-Cl,2,4-di-OMe, 3,4-(OCH₂O) and 3,5-di-Me.

[0239] More favourably, R¹⁰ represents the substituents selected fromthe list consisting of: 2-Br, 2-Cl, 2-F, 2-OMe, 3-Cl, 3-F, 3-Me, 4-Br,4-Cl, 4-I, 2,3-di-F, 2,5-di-F, 2,6-di-F, 3,4-di-F, 3,5-di-F,2,3,5-tri-F, 2,4-di-Cl and 3,5-di-Me.

[0240] Preferably, R¹⁰ represents the substituents selected from thelist consisting of: 2-F, 2-OMe, 3-F, 4-Cl and 2,3-di-F.

[0241] Suitably, R¹¹ represents hydrogen or one or more substituentsselected from the list consisting of: 2-F, 2-Me, 3-Br, 3-Cl, 3-F, 3-I,3-OH, 3-OMe, 3-OPh, 3-SMe, 3-CO₂H, 3-CHCO₂H, 3-CH₂CO₂Me, 3-CH₂CONH₂,3-CH₂CONHMe, 3-CH₂OH, 4-Cl, 4-F, 4-Me, 4-NHCOMe, 4-NHPh, 4-NHSO₂Me,4-NMe₂, 4-OMe, 4-COPh, 4-SMe, 4-CH₂CN, 4-SO₂NH₂, 4-(CH₂)₂OH, 4-CH(OH)Ph,4-CH₂SO₂NHMe, 4-CH₂CO₂H, 4-(CH₂)₂CO₂H, 4-(CH₂)₂CO₂Me, 4-(CH₂)₂CONH₂,4-(CH₂)₃CO₂H, 4-(CH₂)₃CONH₂, 4-CH═CHCO₂H, 4-CH═CHCONH₂, 4-OCH₂CO₂H,4-SCH₂CO₂H, 4-S-[2-CO₂H-Ph], 4-S-[3-CO₂H-Ph],4-CH₂(1,3-thiazolidin-2,4-dion-5-yl), 2,3-di-F, 2,4-di-F, 3,4-di-F,3,5-di-F, 3-Cl-4-Br, 3-Cl-4-Me, 3-Br-4-Me, 3-Cl-4-OH, 3-Cl-4-OMe,3,5-di-Me, 3,5-di-OMe, 3,4-OC(O)NH—, 3,4-OCF₂O—, 3,5-di-Br-4-OH,3,5-di-Cl-4-Me, 3,5-di-Cl-4-OH, 3-CO₂H-4-[S-(2-CO₂H)-Ph],3-CO₂H-4-[S-(2-CONHMe)-Ph], 3-CO₂H-4-Cl, 3-F-4-Me, 3-F-4-OMe,-3,4-[(CH═N—NH)]—, -3,4-[(N═N—NH)]—, -3,4-[(NH—N═CH)]—, -3,4-[(CH₂)₃]—,-3,4-[(O(CH₂)₃O)]—, -3,4-[O—C(NHMe)═N]—, -3,4-[OCH₂O]—,-3,4-[S—C(NHMe)═N]— and -3,4-[S—CH═N]—.

[0242] Favourably, R¹¹ represents hydrogen or the substituents selectedfrom the list consisting of: 2-F, 2-Me, 3-Cl, 3-F, 3-I, 3-OMe, 3-OPh,3-SMe, 3-CH₂CO₂H, 3-CH₂CO₂Me, 3-CH₂CONH₂, 3-CH₂CONHMe, 3-CH₂OH, 4-Cl,4-F, 4-Me, 4-NHCOMe, 4-NHPh, 4-NHSO₂Me, 4-NMe₂, 4-OMe, 4-COPh, 4-SMe,4-CH₂CN, 4-SO₂NH₂, 4-(CH₂)₂OH, 4-CH(OH)Ph, 4-CH₂SO₂NHMe, 4-CH₂CO₂H,4-(CH₂)₂CO₂H, 4-(CH₂)₂CO₂Me, 4-(CH₂)₂CONH₂, 4-(CH₂)₃CO₂H, 4-(CH₂)₃CONH₂,4-CH═CHCONH₂, 4-OCH₂CO₂H, 4-SCH₂CO₂H, 4-S-[2-CO₂H-Ph], 4-S-[3-CO₂H-Ph],4-CH₂ (1,3-thiazolidin-2,4-dion-5-yl), 2,3-di-F, 2,4-di-F, 3,4-di-F,3,5-di-F, 3-Cl-4-Br, 3-Cl-4-Me, 3-Br-4-Me, 3-Cl-4-OH, 3-Cl-4-OMe,3,5-di-Me, 3,5-di-OMe, 3,4-[OC(O)NH], 3,4-[OCF₂O]3,5-di-Cl-4-Me,3-CO₂H-4-[S-(2-CONHMe)-Ph], 3-F-4-Me, 3-F-4-OMe, 3,4-[(CH═N—NH)],3,4-[(N═N—NH)], 3,4-[(NH—N═CH)], 3,4-[(CH₂)₃], 3,4-[O(CH₂)₃O],3,4-[O—C(NHMe)═N], 3,4-[OCH₂O], 3,4-[S—C(NHMe)═N] and 3,4-[S—CH═N].

[0243] More favourably, R¹¹ represents the substituents selected fromthe list consisting of: 3-Cl, 3-Br, 4-OMe, 3,5-di-F, 4-CH₂SO₂NHMe,4-(CH₂)₃CO₂H and 4-S-[3-CO₂H-Ph].

[0244] A particular compound of formula (IC) is that wherein R and R¹each represent hydrogen and R¹⁰ and R¹¹ each have the followingrespective values: R¹⁰ R11 4-Cl 3-Cl 4-Cl 3-Br 2-OMe 4-OMe 4-Cl4-CH₂SO₂NHMe 2-OMe 3,5-di-F 2-F 3,5-di-F 3-F 4-(CH₂)₃CO₂H 2,3-di-F-Ph3,5-di-F.

[0245] It is considered that the compounds of formula (IC′) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IC′) or a derivative thereof.

[0246] There is a subgroup of compounds falling wholly within formula(I) being of formula (ID):

[0247] wherein R and R¹ are as defined in relation to formula (I);

[0248] R^(2′) is phenyl, substituted phenyl or indolyl;

[0249] R^(3′) is hydrogen, alkyl, cycloalkyl, phenyl, substitutedphenyl, C₁₋₆ alkylphenyl wherein the phenyl group is optionallysubstituted, alkoxyalkyl, substituted or unsubstituted heterocyclyl.

[0250] In one aspect, there is provided a compound of formula (I) ashereinbefore defined which excludes compounds of formula (ID).

[0251] There is a subgroup of compounds within formula (ID) of formula(ID′) wherein R, R¹, R^(2′) and R^(3′) are as defined in relation toformula (ID) with the proviso that formula (ID′) does not include thefollowing compounds, hereinafter referred to as List D′:

[0252]3-[2-benzo[b]thien-2-yl-3-[4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]-carbamimidothioicacid,propyl ester;

[0253]3-(dimethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0254] 3-(1H-indol-3-yl)-1-methyl-4-(phenylamino)-1H-pyrrole-2,5-dione;

[0255]3-(1H-indol-3-yl)-1-methyl-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrole-2,5-dione;

[0256] 3-(1H-indol-3-yl)-1-methyl-4-(methylamino)-1H-pyrrole-2,5-dione;

[0257]3-(6-chloro-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0258] 3-(6-amino-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0259]1-acetyl-3-[2,5-dihydro-1-methyl-2,5-dioxo-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrol-3-yl]-1H-indole;

[0260] 3-amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0261] 3-amino-4-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0262] 1H-Indole-1-carboxylic acid,3-(4-amino-2,5-dihydro-1-methyl-2,5-dioxo-1H-pyrrol-3-yl)-,1,1-dimethylethyl ester;

[0263]3-(1H-indol-3-yl)-1-methyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;

[0264] Glycine,N-[2,5-dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl- ,ethyl ester;

[0265] 3-amino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0266]3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0267]3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0268]3-(1H-indol-3-yl)-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;

[0269]1-[3-[(3-aminopropyl)amino]propyl]-3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0270]1-[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]-3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0271]3-(1H-indol-3-yl)-1-[3-(4-methyl-1-piperazinyl)propyl]-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;

[0272]3,3′-[iminobis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0273]3,3′-[1,4-piperazinediylbis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0274] 3-amino-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione;

[0275] 3-[(5-aminopentyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0276]3-[[5-[(2-aminoethyl)amino]pentyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0277] 3-[(2-aminoethyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0278] 3-[(6-aminohexyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0279] 3-[(7-aminoheptyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0280]3-[[2-[(2-aminoethyl)amino]ethyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0281] Benzenepropanamide,.alpha.-amino-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl-, (S)—;

[0282] Pentanoic acid,4-amino-5-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]-5-oxo-, (S)—;

[0283] Pentanamide,2-amino-5-[(aminoiminomethyl)amino]-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl-, (S)—;

[0284] Benzenepropanamide,.alpha.-amino-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl-, (S)—;

[0285] Butanamide,4-[(aminoiminomethyl)amino]-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl)amino]pentyl-, (S)—;

[0286] 3-amino-1,4-diphenyl-1H-pyrrole-2,5-dione;

[0287]3-(4-methylphenyl)-1-phenyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;

[0288] 3-amino-4-(4-methylphenyl)-1-phenyl-1H-pyrrole-2,5-dione;

[0289] 3-amino-1-methyl-4-p-tolyl-1H-pyrrole-2,5-dione;

[0290] 3-(2-diethylamino-ethylamino)-4-phenyl-pyrrole-2,5-dione;

[0291]3-[butyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;

[0292]3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;

[0293]3-[benzyl-(2-dimethylamino-ethyl)-amino]-1-methyl-4-phenyl-pyrrole-2,5-dione;

[0294]3-[benzyl-(2-dimethlamino-ethyl)-amino]-4-(4-chloro-phenyl)-pyrrole-2,5-dione;

[0295]3-[benzyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;

[0296]3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-(3-methoxy-phenyl)-pyrrole-2,5-dione;

[0297]3-(4-chloro-phenyl)-4-[2-(4-methyl-piperazin-1-yl)-ethylamino]-pyrrole-2,5-dione;

[0298]3-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-phenyl-pyrrole-2,5-dione;

[0299] 3-phenyl-4-(diethylamino)-pyrrole-2,5-dione;

[0300] 3-phenyl-4-(benzylamino)-pyrrole-2,5-dione;

[0301] 1-methyl-3-phenyl-4-(2-diethylaminoethylamino)-pyrrole-2,5-dione,and;

[0302] 1-allyl-3-phenyl-4-(2-dimethylaminoethylamino)-pyrrole-2,5-dione.

[0303] Suitably R^(2′) is indolyl, phenyl or phenyl substituted with oneor more, suitably up to three, substituents selected from the listconsisting of: halo, haloalkyl, alkoxy, nitro, alkyl and alkoxy.

[0304] Examples of R^(2′) include phenyl, indol-3-yl, 2-methoxyphenyl,3-fluorophenyl, 3-nitrophenyl, 4-chlorophenyl, 4-iodophenyl,4-(trifluoromethyl)phenyl and 2,3-difluorophenyl.

[0305] Suitably R^(3′) represents hydrogen, C₁₋₆ alkyl, cyclohexyl,phenyl, fluorenyl, C₁₋₂alkylphenyl, C₁₋₆alkoxyC₁₋₂alkyl or a substitutedor unsubstituted single or a single or fused ring heterocyclyl grouphaving 5 or 6 ring atoms and up to 3 hetero atoms in each ring, such asoxazolyl, benzofuranyl, dibenzofuranyl, pyridinyl, quinolinyl,pyrimidinyl.

[0306] Examples of R^(3′) include hydrogen, ethyl, cyclohexyl, phenyl,fluoren-2-yl, benzyl, phenyl(CH₂)₂—, MeO(CH₂)₂—, 4-methyloxazol-2-yl,2-acetylbenzofuran-5-yl, dibenzofuran-2-yl, dibenzofuran-3-yl,2-methylpyridin-3-yl 2,6-dimethylpyridin-3-yl, 2-chloropyridin-5-yl,quinolin-3-yl, pyrimidin-2-yl.

[0307] It is considered that the compounds of formula (ID′) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (ID′) or a derivative thereof.

[0308] There is a subgroup of compounds falling wholly within formula(I) being of formula (IE):

[0309] wherein R is as defined in relation to formula (I);

[0310] R¹⁰ represents hydrogen or one or more, suitably up to three,substituents selected from the list consisting of: alkoxy, halo, andnitro;

[0311] P′-Q′ represents —(CH₂)_(a)O(CH₂)_(b)—, (CH₂)_(a)S(CH₂)_(b)—,—(CH₂)_(c)—, —(CH₂)_(d)CH(G)(CH₂)_(e)—, —(CH₂)_(a)N(ZZ)(CH₂)_(b)—, wherea, b, d, and e are independently 1 to 4, c is 1 to 6, ZZ is hydrogen,alkyl, aryl, or alkylcarbonyl, and G is alkyl, amido, hydroxyalkyl,aralkyl, or hydroxy.

[0312] There is a subgroup of compounds within formula (IE) of formula(IE′) wherein R, R¹⁰, and P′-Q′ are as defined in relation to formula(IE) with the proviso that formula (IE′) does not include:

[0313]3-phenyl-4-piperidin-1-yl-pyrrole-2,5-dione;

[0314] 3-(4-methylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;

[0315] 3-(4-ethylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;

[0316] 3-(4-chlorophenyl)-4-(4-methyl-piperazin-1-yl)-pyrrole-2,5-dione;

[0317]3-(4-methylphenyl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione

[0318] 3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;

[0319] 3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;

[0320] 1-methyl-3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;

[0321] 1-ethyl-3′-phenyl-4-(4-chlorophenylpiperazino)-pyrrole-2,5-dione;

[0322] 1-allyl-3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione, and;

[0323] 1-allyl-3-diphenyl-4-piperidino-pyrrole-2,5-dione.

[0324] Suitably, R^(10′) is methoxy, chloro, or nitro.

[0325] Examples of R^(10′) include 4-methoxy, 4-chloro, 2,4-dichloro,and 3-nitro.

[0326] Examples of —P′-Q′- include —(CH₂)₄—, —(CH₂)₂O(CH₂)₂—,—(CH₂)₃CH(Me)CH₂—, —(CH₂)₃CH(CONH)CH₂—, —(CH₂)₃CH(CH₂OH)CH₂—,—(CH₂)₂CH(CH₂Ph)(CH₂)₂—, —(CH₂)₂CH(OH)(CH₂)₂—, —(CH₂)₅—, and—CH₂)S(CH₂)₂—

[0327] It is considered that the compounds of formula (IE′) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IE′) or a derivative thereof.

[0328] There is a subgroup of compounds falling wholly within formula(I) being of formula (IF):

[0329] wherein R is as defined in relation to formula (I);

[0330] R10″ is one or more, suitably up to three, substituents selectedfrom the list consisting of perfluoroalkyl, halo, nitro, alkoxy,arylcarbonyl, alkyl;

[0331] Z is a bond or an alkylene chain;

[0332] —X—Y— is —CH═N, —(CH₂)_(t)—, —(CH₂)_(u)CH(U)—, —(U)CH(CH₂)_(u)—,—CH═CH—, —(CH₂)_(v)C(alkyl)₂- , —C(O)C(alkyl)₂- , —C(O)O—, where t, u,and v are independently 1 to 4, and U is alkyl, carboxy, alkoxycarbonyl,hydroxyalkyl, and amido;

[0333] R^(12a′), R^(12b′), and R^(12c′) are each independently hydrogen.nitro, alkoxy, 4-ethylpiperazin-1-yl, 4-BOC-piperazin-1-yl,4-methyl-piperazin-1-yl, 4-methyl-piperazin-1-yl, halo, alkyl,piperazin-1-yl, perfluoroalkyl, and alkylsulphonylamino.

[0334] Suitably, Z is a bond or a C₁₋₂ alkylene chain.

[0335] Examples of Z include a bond, methylene or ethylene.

[0336] Examples of —X—Y— are —CH═N—, —(CH₂)₂—, —CH(Me)CH₂—, —CH═CH—,—CH(CO₂H)CH₂—, —CH(CO₂Me)CH₂—, —(CH₂)₃—, —CH(CH₂OH)CH₂—, —CH₂CH(CH₂OH)—,—CH₂CHMe)—, —CH₂C(Me)₂—, —CH(CONH₂)CH₂—, —C(O)C(Me)₂—, and —C(O)O—

[0337] Examples of R^(12a′), R^(12b′), and R^(12c′) include hydrogen,nitro, fluoro, methoxy, 4-ethylpiperazin-1-yl, 4-BOC-piperazin-1-yl,4-methyl-piperazin-1-yl, 4-methyl-piperazin-1-yl, chloro, bromo,trifluoromethyl, and methanesulphonylamino.

[0338] Preferably, Z is a bond.

[0339] Preferably, —X—Y— is —(CH₂)₂— or —CH(CH₂OH)CH₂—, —CH(Me)CH₂—,—CH₂CH(Me)—, or —CH₂C(Me)₂—.

[0340] Preferably, R^(12b′) is fluorine.

[0341] Preferably, R^(12a′) is fluorine.

[0342] Most preferably, R^(10″) is 2-Br, 2-Cl, 2-F, 2-OMe, 3-Cl, 3-F,3-Me, 4-Br, 4-Cl, 4-I, 2,3-di-F, 2,5-di-F, 2,6-di-F, 3,4-di-F, 3,5-di-F,2,3,5-tri-F, 2,4-di-Cl, 3,5-di-Me;

[0343] Z is a bond:

[0344] —X—Y— is —(CH₂)₂— or —CH(CH₂OH)CH₂—, —CH(Me)CH₂—, —CH₂CH(Me)—, or—CH₂C(Me)₂—,

[0345] R^(12b′) is fluorine; and

[0346] R^(12a′) is fluorine.

[0347] It is considered that the compounds of formula (IF) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IF) or a derivative thereof.

[0348] There is a subgroup of compounds falling wholly within formula(I) being of formula (IG):

[0349] wherein R and R¹ are as defined in relation to formula (I);

[0350] A is N(alkyl), oxygen, or sulphur.

[0351] Examples of A are N(methyl), oxygen, and sulphur.

[0352] Preferably, A is sulphur.

[0353] R^(11″) is one or more, suitably up to three, substituentsselected from the group consisting of hydrogen, halo, alkyl, alkylthio,—S—CH═N—, phenoxy, —(CH₂)_(w)—, hydroxy, carboxy, —O(CH₂)_(x)O—,hydroxyalkyl, and alkylaminosulphonylalkyl, where w and x areindependently 1 to 4.

[0354] Examples of R^(11″) are hydrogen, bromo, methyl, methylthio,chloro, —S—CH═N—, phenoxy, —(CH₂)₃—, hydroxy, carboxy, —O(CH₂)O—,fluoro, hydroxymethyl, and MeNHSO₂CH₂—.

[0355] Preferably, R^(11″) is 3-Br, 4-Me, 4-SMe, 3-Br-4-Me, 3-Cl,3,4-[S—CH═N]—, 3-OPh, 3,4-[(CH₂)₃]—, 3-SMe, hydrogen, 3,5-diBr-4-OH,3,5-diCl-4-OH, 3-CO₂H-4-Cl, 3,4-[-OCH₂O]—, 3-Cl-4-OH, 3,5-diF, 3-CH₂OH,3-OH, or 4-CH₂SO₂NHMe.

[0356] R^(13′) is one or more, suitably up to two, substituents selectedfrom the group consisting of —(CH═CH)₂— and hydrogen.

[0357] Examples of R^(13′) include 4,5-[(CH═CH)₂— and hydrogen.

[0358] Preferably, R^(13′) is hydrogen.

[0359] It is considered that the compounds of formula (IG) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IG) or a derivative thereof.

[0360] There is a subgroup of compounds falling wholly within formula(I) being of formula (IH):

[0361] wherein R and R¹ are as defined in relation to formula (I);

[0362] R^(11′″) is —[(CH₂)_(aa)]—, where aa is 1 to 4;

[0363] R^(14′) is hydrogen;

[0364] R^(15′) is alkyl, unsubstituted or substituted phenylamino,unsubstituted or substituted phenylalkylamino, cyclohexylamino,alkenylamino, phenyl, benzyl, styryl, or alkylamino.

[0365] Examples of R^(11′″) include 3,4-[(CH₂)₃].

[0366] Suitably, R^(15′) is C₁₋₆alkyl, (halophenyl)amino,phenylalkylamino. cyclohexylamino, propenylamino, phenyl, benzyl,styryl, propyl, ethylamino, or (methoxyphenyl)amino.

[0367] Examples of R^(15′) include methyl, (3-fluorophenyl)amino,phenylethylamino, cyclohexylamino, propenylamino, phenyl, benzyl,trans-styryl, n-propyl, ethylamino, and (3-methoxyphenyl)amino.

[0368] It is considered that the compounds of formula (IH) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IH) or a derivative thereof.

[0369] There is a subgroup of compounds falling wholly within formula(I) being of formula (IJ):

[0370] wherein R and R¹ are as defined in relation to formula (I);

[0371] R^(10′″) represents one or more, suitably up to three,substituents independently selected from alkoxy or halo;

[0372] R^(16′) represents one or more, suitably up to three,substituents independently selected from hydrogen, carboxy,alkoxycarbonyl, or alkylaminocarbonyl;

[0373] R^(17′) represents one or more, suitably up to three,substituents independently selected from carboxy, alkoxycarbonyl, halo,alkylaminocarbonyl, nitro, or hydrogen;

[0374] W is sulphur, oxygen, or substituted or unsubstituted NH.

[0375] Suitably, W is sulphur or oxygen. Favourably, W is sulphur.

[0376] Suitably, R^(10′″) is C₁₋₆alkoxy, chloro, or fluoro.

[0377] Examples of R^(10′″) are methoxy, 4-chloro, 2-chloro, and2,3-difluoro.

[0378] Favourably, R^(10′″) is 2,3-difluoro.

[0379] Suitably, R^(16′) is hydrogen, carboxy, C₁₋₆alkoxycarbonyl, orC₁₋₆alkylaminocarbonyl.

[0380] Examples of R^(16′) are carboxy, hydrogen, ethoxycarbonyl,methoxycarbonyl, and methylaminocarbonyl.

[0381] Favourably, R^(16′) is hydrogen.

[0382] Suitably, R^(17′) is carboxy, C₁₋₆alkoxycarbonyl, halo,C₁₋₆alkylaminocarbonyl, nitro, or hydrogen;

[0383] Examples of R^(17′) are 2-carboxy, 3-carboxy, 4-carboxy,4-chloro,

[0384] 2-methylaminocarbonyl, 4-nitro, hydrogen, and 2-ethoxycarbonyl.

[0385] Favourably, R^(17′) is 3-carboxy.

[0386] It is considered that the compounds of formula (IJ) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IJ) or a derivative thereof.

[0387] There is a subgroup of compounds falling wholly within formula(I) being of formula (IK):

[0388] wherein R and R¹ are as defined in relation to formula (I);

[0389] R^(11″″) represents one or more, suitably up to three,substituents independently selected from halo and hydroxy;

[0390] R^(18′) represents one or more, suitably up to three,substituents independently selected from hydrogen, alkyl, and —CH═CH)₂—;

[0391] A is sulphur.

[0392] Suitably, R^(11″″) is chloro or hydroxy.

[0393] Examples of R^(11″″) are 3-chloro and 3,5-dichloro4-hydroxy.

[0394] Suitably, R^(18′) is hydrogen, C₁₋₆alkyl, or —(CH═CH)₂—.

[0395] Examples of R^(18′) include hydrogen, methyl, and3-methyl-4,5-[(CH═CH)₂]—,

[0396] It is considered that the compounds of formula (IK) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IK) or a derivative thereof.

[0397] There is a subgroup of compounds falling wholly within formula(I) being of formula (IL):

[0398] wherein R is as defined in relation to formula (I);

[0399] R^(2′″) is unsubstituted or substituted heterocyclyl orunsubstituted or substituted aryl;

[0400] R^(19′) is unsubstituted or substituted heterocyclyl, or aquatemised salt thereof.

[0401] There is a subgroup of compounds within formula (IL) of formula(IL′) wherein R, R^(2′″), and R^(19′) are as defined in relation toformula (IL) with the proviso that (IL′) does not include the followingcompounds, hereinafter referred to as List L′:

[0402] 3-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;

[0403]1-(1-methyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0404]1-1-(4-methyl-pentyl)-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0405]1-(1-dodecyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridiniumchloride;

[0406]3-[2,5-dihydro-4-(1H-imidazol-1-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-1H-indole-1-carboxylicacid, 1,1-dimethylethyl ester;

[0407]3-(1H-imidazo[4,5-b]pyridin-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0408]3-(1H-indol-3-yl)-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione;

[0409]3-(1H-indol-3-yl)-1-methyl-4-(1-piperidinyl)-1H-pyrrole-2,5-dione;

[0410]3-[4-(diphenylmethyl)-1-piperazinyl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0411]3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0412]3-(1H-benzotriazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0413]3-(1H-imidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0414]3-(1H-indol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0415]3-(1H-indazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0416]3-[3-[(dimethylamino)methyl]-1H-indol-1-yl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;

[0417] 3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;

[0418]3-(1H-indol-1-yl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione, and;

[0419]3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione.

[0420] Suitably, R^(2′″) is thienyl, phenyl, or phenyl substituted withone or more halogen groups.

[0421] Examples of R^(2′″) include phenyl, 3-thienyl, 2-thienyl,4-chlorophenyl, and 2,4-dichlorophenyl.

[0422] Favourably, R^(2′″) is phenyl, 3-thienyl, 4-chlorophenyl, or2,4-dichlorophenyl.

[0423] Suitably, R^(19′) is indolinyl, pyridinium halide,azabicyclooctanyl, or triazaspirodecanonyl.

[0424] Examples of R^(19′) include indolin-1-yl, 3-amino-1-pyridiniumchloride, 2-methylindolin-1-yl,1,3,3-trimethyl-6-azabicyclo[3,2,1]octan-6-yl, and1-phenyl-1,3,8-triazaspiro-[4,5]-decan-4-one-8-yl.

[0425] Favourably, R^(19′) is indolin-1-yl, or 2-methylindolin-1-yl.

[0426] It is considered that the compounds of formula (IL′) are novel.Accordingly, the present invention also provides a compound of the abovedefined formula (IL′) or a derivative thereof.

[0427] Certain of the compounds of formula (I) may contain at least onechiral carbon, and hence they may exist in one or more stereoisomericforms. The present invention encompasses all of the isomeric forms ofthe compounds of formula (I) whether as individual isomers or asmixtures of isomers, including racemates.

[0428] Alkyl groups referred to herein, including those forming part ofother groups, include straight or branched chain alkyl groups containingup to six carbon atoms, said carbon atoms being optionally substitutedwith up to five, suitably up to three, groups selected from the listconsisting of aryl, heterocyclyl, alkylthio, alkenylthio, alkynylthio,arylthio, heterocyclylthio, alkoxy, arylalkoxy, arylalkylthio, amino,mono- or di-alkylamino, cycloalkyl, cycloalkenyl, carboxy and estersthereof, phosphonic acid and esters thereof, mono- ordialkylaminosulphonyl, aminosulphonyl, cyano, alkylcarbonylamino,arylcarbonylamino, hydroxy, and halogen.

[0429] Alkenyl and alkynyl groups referred to herein include straightand branched chain alkenyl groups containing from two to six carbonatoms, said carbon atoms being optionally substituted with up to five,suitably up to three, groups including those substituents describedhereinbefore for the alkyl group.

[0430] Cycloalkyl and cycloalkenyl groups referred to herein includegroups having between three and eight ring carbon atoms, which carbonatoms are optionally substituted with up to five, suitably up to three,groups including those substituents described hereinbefore for the alkylgroup.

[0431] When used herein the term “aryl” includes phenyl and biphenylgroups, for example naphthyl, especially phenyl.

[0432] Suitably optional substituents for any aryl group include up tothree substituents selected from the list consisting of halo, alkyl,alkenyl, substituted alkenyl, arylalkyl, alkoxy, alkoxyalkyl, haloalkyl,haloalkyloxy, hydroxy, hydroxyalkyl, nitro, amino, cyano, cyanoalkyl,mono-and di-N-alkylamino, acyl, acylamino, N-alkylacylamino, acyloxy,carboxy, carboxyalkyl, carboxyalkylcarbonyl, carboxyalkenyl,ketoalkylester, carbamoyl, carbamoylalkyl, mono-and di-N-alkylcarbamoyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxy, arylthio, aralkyloxy,aryloxycarbonyl, ureido, guanidino, morpholino, adamantyl, oxazolyl,aminosulphonyl, alkylaminosulphonyl, alkylthio, haloalkylthio,alkylsulphinyl, alkylsulphonyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, trityl, substituted trityl, mono- orbis-alkylphosphonate or mono- or bis-alkylphosphonateC₁₋₆alkyl or anytwo adjacent substituents on the phenyl ring together with the carbonatoms to which they are attached form a carbocyclic ring or aheterocyclic ring.

[0433] When used herein the terms “heterocyclyl” and “heterocyclic”suitably include, unless otherwise defined, aromatic and non-aromatic,single and fuised, rings suitably containing up to four heteroatoms ineach ring, each of which is selected from oxygen, nitrogen and sulphur,which rings, may be unsubstituted or substituted by, for example, up tothree substituents. Each ring suitably has from 4 to 7, preferably 5 or6, ring atoms. A fused heterocyclic ring system may include carbocyclicrings and need include only one heterocyclic ring.

[0434] Substituents for any heterocyclyl or heterocyclic group aresuitably selected from halogen, alkyl, arylalkyl, alkoxy, alkoxyalkyl,haloalkyl, hydroxy, amino, mono-and di-N-alkyl-amino, acylamino, carboxysalts. carboxy esters, carbamoyl, mono-and di-N-alkylcarbonyl,aryloxycarbonyl, alkoxycarbonylalkyl, aryl, oxy groups, ureido,guanidino, sulphonylamino, aminosulphonyl, alkylthio, alkylsulphinyl,alkylsulphonyl, heterocyclyl and heterocyclylalkyl.

[0435] When used herein ‘halo’ includes iodo, bromo, chloro or fluoro,especially chloro or fluoro.

[0436] Suitable derivatives of the compounds of the invention arepharmaceutically acceptable derivatives.

[0437] Suitable derivatives of the compounds of the invention includesalts and solvates.

[0438] Suitable pharmaceutically acceptable derivatives includepharmaceutically acceptable salts and pharmaceutically acceptablesolvates.

[0439] Suitable pharmaceutically acceptable salts include metal salts,such as for example aluminium, alkali metal salts such as lithium,sodium or potassium, alkaline earth metal salts such as calcium ormagnesium and ammonium or substituted ammonium salts, for example thosewith lower alkylamines such as triethylamine, hydroxy alkylamines suchas 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

[0440] Suitable pharmaceutically acceptable salts also includespharmaceutically acceptable acid addition salts. such as those providedby pharmaceutically acceptable inorganic acids or organic acids.

[0441] Suitable pharmaceutically acceptable acid addition salts providedby pharmaceutically acceptable inorganic acids includes the sulphate,nitrate, phosphate, borate, hydrochloride and hydrobromide andhydroiodide.

[0442] Suitable pharmaceutically acceptable acid addition salts providedby pharmaceutically acceptable organic acids includes the acetate,tartrate, maleate, fumarate, malonate, citrate, succinate, lactate,oxalate, benzoate, ascorbate, methanesulphonate, α-keto glutarate andα-glycerophosphate.

[0443] Suitable pharmaceutically acceptable solvates include hydrates.

[0444] For the avoidance of doubt when used herein the term “diabetes”includes diabetes mellitus, especially Type 2 diabetes, and conditionsassociated with diabetes mellitus.

[0445] The term ‘conditions associated with diabetes’ includes thoseconditions associated with the pre-diabetic state, conditions associatedwith diabetes mellitus itself and complications associated with diabetesmellitus.

[0446] The term ‘conditions associated with the pre-diabetic state’includes conditions such as insulin resistance, impaired glucosetolerance and hyperinsulinaemia.

[0447] The term ‘conditions associated with diabetes mellitus itself’include hyperglycaemia, insulin resistance and obesity. Furtherconditions associated with diabetes mellitus itself include hypertensionand cardiovascular disease, especially atherosclerosis and conditionsassociated with insulin resistance. Conditions associated with insulinresistance include polycystic ovarian syndrome and steroid inducedinsulin resistance.

[0448] The term ‘complications associated with diabetes mellitus’includes renal disease, especially renal disease associated with Type IIdiabetes, neuropathy and retinopathy, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease.

[0449] A further aspect of the invention provides a process for thepreparation of a compound of the invention, which process comprisesreaction of a compound of formula (II):

[0450] wherein R and R² are as defined in formula (I) and L is a leavinggroup, with a compound of formula (III):

[0451] wherein R¹ and R³ are as defined in formula (I); and thereafter,if required, carrying out one or more of the following optional steps:

[0452] (i) converting a compound of formula (I) to a further compound offormula (I);

[0453] (ii) removing any necessary protecting group;

[0454] (iii) preparing an appropriate derivative of the compound soformed.

[0455] Examples of suitable leaving groups, L, are chloro, bromo,triflate, and hydroxy.

[0456] The reaction between the compounds of formulae (II) and (III) iscarried out in any suitable solvent, for example1-methyl-2-pyrrolidinone, tetrahydrofuran, 0.880 ammonia, or methanol,under conventional amination conditions at any temperature providing asuitable rate of formation of the required product, generally anelevated temperature, over a suitable reaction time.

[0457] Suitable reaction temperatures include those in the range of 60°C. to 220° C. and, as appropriate, the reflux temperature of thesolvent. When the compound of formula (III) is a weak nucleophile, thenthe reaction may be assisted by, for example, using temperatures at theupper end of this range, generating the anion of the compound of formula(III) in sites using, for example, sodium hydride, or by using a basiccatalyst such as triethylamine. Conventional methods of heating alsoinclude the use of microwave heating devices, for example a microwavereactor, such as a 100 watt reactor.

[0458] The reaction products are isolated using conventional methods.Typically, the reaction mixture is cooled, the residue acidified and theproducts extracted using solvent extraction, suitably using an organicsolvent.

[0459] The reaction products are purified by conventional methods, suchas chromatography and trituration.

[0460] Crystalline product may be obtained by standard methods.

[0461] Crystalline product may be obtained by standard methods.

[0462] In a preferred aspect, a solution of the compound of formula (II)and a compound of formula (III) in methanol is heated to reflux frombetween 1 to 4 days, then cooled and concentrated. The residue is thenacidified with hydrochloric acid, and extracted with ethyl acetate. Theorganic extracts are then washed with water, brine, dried with anhydrousmagnesium sulphate, and the solvent is removed. The product is thenpurified by standard methods such as trituration or chromatography, onsilica gel, to afford the desired compound.

[0463] The above mentioned conversion of a compound of formula (I) intoanother compound of formula (I) includes any conversion which may beeffected using conventional procedures, but in particular the saidconversions include any combination of:

[0464] i) converting one group R into another group R;

[0465] (ii) converting one group R³ into another group R³;

[0466] (iii) converting one group R¹⁰ into another group R¹⁰, and;

[0467] (iv) converting one group R¹¹ into another group R¹¹.

[0468] The above mentioned conversions (i) to (iv) may be carried outusing any appropriate method under conditions determined by theparticular groups chosen.

[0469] Thus, suitable conversions of one group R into another group R,as in conversion (i), include:

[0470] (a) converting a group R which represents hydrogen into a group Rwhich represents an alkyl or arylalkyl group; such conversion may becarried out using an appropriate conventional alkylation procedure, forexample treating an appropriately protected compound of formula (I) withan alkylating agent; and

[0471] (b) converting a group R which represents an alkyl group into agroup R where R represents hydrogen; such conversion may be carried outusing an appropriate dealkylation procedure, for example treating anappropriately protected compound of formula (I) with aqueous basefollowed bv ammonium hydroxide.

[0472] Suitable conversions of one group NR¹R³ into another group NR¹R³,as in conversion (ii), include:

[0473] converting a group NR¹R³ which represents arylamino into anothergroup NR¹R³ which represents alkylamino; such conversion may be carriedout using an appropriate conventional procedure, for example treating anappropriately protected compound of formula (I) with an alkylamine.

[0474] Suitable conversions of one group R¹⁰ into another group R¹⁰, asin conversion (iii), include:

[0475] (a) converting a group R¹⁰ which represents nitro into a groupR¹⁰ which represents amino, such conversion may be carried out using aconventional reduction procedure, for example hydrogenating anappropriately protected compound of formula (I);

[0476] (b) converting a group R¹⁰ which represents nitro into a groupR¹⁰ which represents acetylamino, such conversion may be carried outusing an appropriate conventional reductive acylation procedure, forexample hydrogenating an appropriately protected compound of formula (I)followed by acylation of the resultant amino group with an acylatingagent;

[0477] (c) converting a group R¹⁰ which represents amino into a groupR¹⁰ which represents a substituted urea, such conversion may be carriedout using an appropriate conventional amidation procedure, for exampletreating an appropriately protected compound of formula (I) with anappropriately substituted isocyanate;

[0478] (d) converting a group R¹⁰ which represents amino into a groupR¹⁰ which represents acylamino, such conversion may be carried out usingan appropriate conventional acylation procedure, for example treating anappropriately protected compound of formula (I) with an acylating agent,or treating an appropriately protected compound of formula (I) with asuitable carboxylic acid in the presence of activating agents such as amixture of 1-hydroxybenzotriazole and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and;

[0479] (e) converting a group R¹⁰ which represents iodo into a group R¹⁰which represents alkoxycarbonyl, such conversion may be carried outusing an appropriate procedure, for example treating an appropriatelyprotected compound of formula (I) with carbon monoxide and methanol inthe presence of a palladium (0) complex.

[0480] Suitable conversions of one group R¹¹ into another group R¹¹, asin conversion (iv), include:

[0481] (a) converting a group R¹¹ which represents a t-BOC-protectedamino group-into a group R¹¹ which represents amino, such conversion maybe carried out using an appropriate conventional deprotection procedure,for example deprotecting a t-BOC-protected compound of formula (I) withtrifluoroacetic acid;

[0482] (b) converting a group R¹¹ which represents a carboxylic acidgroup into a group R¹¹ which represents an amide group, such conversionmay be carried out using an appropriate conventional procedure, forexample treating an appropriately protected compound of formula (I) withan amine in the presence of suitable activating agents such as a mixtureof 1-hydroxybenzotriazole and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; and

[0483] (c) converting a group R¹¹ which represents alkoxycarbonyl into agroup R¹¹ which represents carbamoyl, such conversion may be carried outusing an appropriate conventional procedure, for example treating anappropriately protected compound of formula (I) with methanolic ammoniasolution followed by aqueous ammonia.

[0484] The above mentioned conversions may as appropriate be carried outon any of the intermediate compounds mentioned herein.

[0485] Suitable protecting groups in any of the above mentionedreactions are those used conventionally in the art The methods offormation and removal of such protecting groups are those conventionalmethods appropriate to the molecule being protected. Thus for example abenzyloxy group may be prepared by treatment of the appropriate compoundwith a benzyl halide, such as benzyl bromide, and thereafter, ifrequired, the benzyl group may be conveniently removed using catalytichydrogenation or a mild ether cleavage reagent such as trimethylsilyliodide or boron tribromide.

[0486] Where appropriate individual isomeric forms of the compounds offormula (I) may be prepared as individual isomers using conventionalprocedures.

[0487] The absolute stereochemistry of compounds may be determined usingconventional methods, such as X-ray crystallography.

[0488] The derivatives of the compounds of formula (I), including saltsand/or solvates, may be prepared and isolated according to conventionalprocedures.

[0489] The compounds of formula (II) are known compounds or they may beprepared using methods analogous to those used to prepare such compoundssuch as those described in International Patent Application. PublicationNumber WO97/34890 and Wiley, R. H. and Slaymaker. S. C. J. Am. Chem.Soc. (80) 1385 (1958). The compounds of formula (II) may beinter-converted in an analogous manner to the above mentionedinter-conversions of the compounds of formula (I).

[0490] The compounds of formula (III) are either commercially available,or are reported in the chemical literature, or are prepared by analogywith known conventional literature procedures, for example thosedisclosed in Chem. Ber., 1892, 25, 2977, J. Amer. Chem. Soc., 1948, 70,4174-4177, Synthesis 1977, 859, J. Med. Chem., 1994, 37, 3956. Synthesis1994, 1413, and Tetrahedron, 1991, 47, 266 1, or in standard referencetexts of synthetic methodology such as J. March, Advanced OrganicChemistry, 3rd Edition (1985). Wiley Interscience.

[0491] As stated above, the compounds of formula (I), orpharmaceutically acceptable derivatives thereof, are indicated to beuseful as inhibitors of glycogen synthase kinase-3.

[0492] Thus the present invention further provides a compound of formula(I), or a pharmaceutically acceptable derivative thereof, for use as aninhibitor of glycogen synthase kinase-3, and especially for use in thetreatment of conditions associated with a need for the inhibition ofglycogen synthase kinase-3, such as diabetes, especially Type 2diabetes, dementias, such as Alzheimer's disease and manic depression.

[0493] The present invention also provides the use of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, forthe manufacture of a medicament for the treatment of conditionsassociated with a need for the inhibition of glycogen synthase kinase-3,such as diabetes, especially Type 2 diabetes, dementias, such asAlzheimer's disease and manic depression.

[0494] As indicated above, formula (I) comprises a sub-group ofcompounds of formula (IA). In a further aspect of this invention, thereis provided a compound of formula (IA), or a pharmaceutically acceptablederivative thereof, for use as an active therapeutic substance.

[0495] Accordingly, the invention also provides a pharmaceuticalcomposition which comprises a compound of formula (IA), or apharmaceutically acceptable derivative thereof, and a pharmaceuticallyacceptable carrier.

[0496] Preferably, the compounds of formula (I), or pharmaceuticallyacceptable derivatives thereof are administered as pharmaceuticallyacceptable compositions.

[0497] As indicated above it is considered that GSK-3 inhibitors per seare potentially useful in the treatment and/or prophylaxis of mooddisorders, such as schizophrenia, neurotraumatic diseases, such as acutestroke, and for the treatment and/or prophylaxis of cancer and hairloss.

[0498] Accordingly, in a further aspect the invention provides a methodfor the treatment and/or prophylaxis of mood disorders, such asschizophrenia, in a mammal, such as a human, which method comprises theadministration of a pharmaceutically acceptable amount of a GSK-3inhibitor.

[0499] The invention also provides a method for the treatment and/orprophylaxis of neurotraumatic diseases in a mammal, such as a human,which method comprises the administration of a pharmaceuticallyacceptable amount of a GSK-3 inhibitor.

[0500] Neurotraumatic diseases include both open or penetrating headtrauma, such as caused by surgery, or a closed head trauma injury, suchas caused by an injury to the head region ischaemic stroke, includingacute stroke, particularly to the brain area, transient ischaemicattacks following coronary by-pass and cognitive decline following othertransient ischaemic conditions.

[0501] Further provided is a method for the treatment and/or prophylaxisof cancer, in a mammal, such as a human, which method comprises theadministration of a pharmaceutically acceptable amount of a GSK-3inhibitor.

[0502] In addition there is provided a method for the treatment and/orprophylaxis of hair-loss, in a mammal, such as a human, which methodcomprises the administration of a pharmaceutically acceptable amount ofa GSK-3 inhibitor.

[0503] Thus, the invention also provides the use of a GSK-3 inhibitorfor the manufacture of a medicament for the treatment and/or prophylaxisof mood disorders, schizophrenia, neurotraumatic diseases, cancer orhair-loss.

[0504] A suitable GSK-3 inhibitor is a compound of formula (I) or apharmaceutically acceptable derivative thereof.

[0505] The active compounds are usually administered as the solemedicament agent but they may be administered in combination with othermedicament agents as dictated by the severity and type of disease beingtreated. For example in the treatment of diabetes, especially Type 2diabetes, a compound of formula (I), or a pharmaceutically acceptablederivative thereof, may be used in combination with other medicamentagents, especially antidiabetic agents such as insulin secretagogues,especially sulphonylureas, insulin sensitisers, especially glitazoneinsulin sensitisers (for example thiazolidinediones), or with biguanidesor alpha glucosidase inhibitors or the compound of formula (I), or apharmaceutically acceptable derivative thereof, may be administered incombination with insulin.

[0506] The said combination comprises co-administration of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, and anadditional medicament agent or the sequential administration of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, and the additional medicament agent.

[0507] Co-administration includes administration of a pharmaceuticalcomposition which contains both a compound of formula (I), or apharmaceutically acceptable derivative thereof, and the additionalmedicament agent or the essentially simultaneous administration ofseparate pharmaceutical compositions of a compound of formula (I), or apharmaceutically acceptable derivative thereof, and the additionalmedicament agent.

[0508] The compositions of the invention are preferably adapted for oraladministration.

[0509] However, they may be adapted for other modes of administration.

[0510] The compositions may be in the form of tablets, capsules,powders, granules, lozenges, suppositories, reconstitutable powders, orliquid preparations, such as oral or sterile parenteral solutions orsuspensions.

[0511] In order to obtain consistency of administration it is preferredthat a composition of the invention is in the form of a unit dose.

[0512] Preferably the composition are in unit dosage form. A unit dosewill generally contain from 0.1 to 1000 mg of the active compound.

[0513] Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 800 mg/kg/day.

[0514] Suitable dose forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

[0515] The solid oral compositions may be prepared by conventionalmethods of blending, filling or tabletting. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

[0516] Oral liquid preparations may be in the form of, for example,emulsions, syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxvethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol: preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

[0517] For parenteral administration, fluid unit dosage forms areprepared utilizing the compound and a sterile vehicle, and, depending onthe concentration used, can be either suspended or dissolved in thevehicle. In preparing solutions the compound can be dissolved in waterfor injection and filter sterilized before filling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

[0518] The formulations mentioned herein are carried out using standardmethods such as those described or referred to in reference texts suchas the British and US Pharmacopoeias, Remington's PharmaceuticalSciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia(London, The Pharmaceutical Press) or the above mentioned publications.

[0519] Suitable methods for preparing and suitable unit dosages for theadditional medicarnent agent, such as the antidiabetic agent mentionedherein include those methods and dosages described or referred to in theabove mentioned reference texts.

[0520] GSK-3 Assays

[0521] Types of GSK-3 assay used to test the compounds of the inventioninclude the following:

[0522] Type 1: The GSK-3 specific peptide used in this assay was derivedfrom the phosphorylation site of glycogen synthase and its sequence is:

[0523] YRRAAVPPSPSLSRHSSPHQ(S)EDEEE. (S) is pre-phosphorylated as isglycogen synthase in vivo and the three consensus sites for GSK-3specific phosphorylation are underlined. The buffer used to make up theglycogen synthase peptide and [γ-³³P] ATP consisted of MOPS 25 mM, EDTA0.2 mM, MgAcetate 10 mM, Tween-20 0.01% and mercaptoethanol 7.5 mM at pH7.00.

[0524] The compounds were dissolved in dimethyl sulphoxide (DMSO) to afinal concentration of 100 mM. Various concentrations were made up inDMSO and mixed with the substrate (GSK-3 peptide) solution (to a finalconcentration 20 uM) described in the above section along with rabbit orhuman GSK-3α and GSK-3β (final concentration 0.5 U/ml enzyme). Thereactions were initiated with the addition of [γ-³³P] ATP (500cpm/pmole) spiked into a mixture of ATP (final concentration of 10 μM).After 30 min at room temperature the reaction was terminated by theaddition of 10 μl of H₃PO₄/0.01% Tween-20 (2.5%). A volume (10 μl) ofthe mixture was spotted onto P-30 phosphocellulose paper (Wallac &Berthold, EG & G Instruments Ltd, Milton Keynes). The paper was washedfour times in H₃PO₄ (0.5%), 2 mins for each wash, air dried and theradioactive phosphate incorporated into the synthetic glycogen synthasepeptide, which binds to the P-30 phosphocellulose paper, was counted ina Wallac microbeta scintillation counter.

[0525] Analysis of Data: Values for IC₅₀ for each inhibitor werecalculated by fitting a four-parameter logistic curve to the model:cpm=lower+(upper-lower)/(1+(concentration/IC₅₀)^(slope)).

[0526] Type 2: This protocol is based on the ability of the kinase tophosphorylate a biotinylated 26 mer peptide, sequence of which derivedfrom the phosphorylation site of glycogen synthase and its sequence isBiot-YRRAAVPPSPSLSRHSSPHQ(S)EDEEE, with (S) is a pre-phosphorylatedserine as is glycogen synthase in vivo and the three consensus sites forGSK-3 specific phosphorylation are underlined. The phosphorylatedbiotinylated peptide is then captured onto streptavidin coated SPA beads(Amersham Technology), where the signal from the 33P is amplified viathe scintillant contained in the beads.

[0527] The kinase was assayed at a concentration of 10 nM final in 25 mMMOPS buffer, pH 7.0 containing 0.01% Tween-20, 7.5 mM 2-mercaptoethanol,10 mM Magnesium acetate. and 10 uM [γ-³³P]-ATP. After 60 minutesincubation at room temperature, the reaction was stopped by addition of50 mM EDTA solution containing the Streptavidin coated SPA beads to givea final 0.5 mgs of beads per assay well in a 384 microtiter plateformat.

[0528] 10 mM stock solutions of the compounds of the invention in 100%DMSO are generated as a first step in the screening process. The secondstep involves the creation of dose response plates where these compoundsare diluted across the plate where the final low and high concentrationsare to be 0.008 and 10 uM final in the kinase assay. The third stepinvolves the creation of the assay plates. This is achieved bytransferring the compounds from four 96 dose response plates to one 384assay plate on the Robocon Robolab system. The fourth step is to performthe assay as described and count the resulting plates in the Trilux(Wallac 1450 microbeta liquid scintillation and luminescence counter).The final step is data acquisition and analysis where IC₅₀ values aregenerated for each compound in duplicate by fitting a four parameterlogistic curve to the model:cpm=lower+(upper-lower)/(1+(concentration/IC₅₀)^(slope)) in a batchmanner.

[0529] The most potent compounds of the present invention show IC₅₀values in the range of from between 10 to 100 nM.

[0530] No adverse toxicological effects are expected for the compoundsof the invention, when administered in accordance with the invention.

[0531] The following Examples illustrate the invention, but do not limitit in any way.

EXAMPLE 1

[0532] 3-(3-Bromophenylamino)-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione

[0533] A solution of 3-bromoaniline (2.27 mL, 0.020 mol) and3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (2.02 g, 0.0083 mol;prepared by analogy with the methods described in WO97/34890 and Wiley,R. H. and Slaymaker, S. C. J. Am. Chem. Soc. (80) 1385 (1958)) inmethanol (50 mL) was heated at reflux for 40 hours. cooled andconcentrated. The residue was acidified with aqueous hydrochloric acid(1M, 200 mL) and extracted with ethyl acetate (3×200 mL). The combinedorganic solutions were washed with water and brine, dried with magnesiumsulphate, evaporated and the residue chromatographed on silica gel usingdichloromethane-diethyl ether (gradient from 100:0 to 95:5 v/v) aseluent to afford the title compound as a solid.

[0534]¹H NMR (DMSO-d₆): δ6.70-7.30 (8H, m), δ9.65 (1H, br), δ10.90 (1H,br).

[0535] MS (APCI+ve): [M+H]⁺ at m/z 377/379/381 (C₁₆H₁₀BrClN₂O₂ requires[M+H]⁺ at m/z 377/379/38 1).

EXAMPLE 2

[0536] 3-(4-Benzoylphenylamino)-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione

[0537] A sealed tube (comprising threaded glass tube with resealablecap) containing a mixture of 4-aminobenzophenone (0.147 g, 0.75 mmol),3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (0.061 g, 0.25 mmol)and 1-methyl-2-pyrrolidinone (0.5 mL) was irradiated in a microwavereactor for 12 minutes at 100 Watts. The mixture was diluted withaqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (2×5mL). The combined organic solutions were evaporated and the residuechromatographed on silica gel using dichloromethane as eluent to affordthe title compound as a solid.

[0538]¹H NMR (DMSO-d₆): δ6.85 (2H, d), δ7.00 (2H, d), δ7.25 (2H, d),δ7.35 (2H, d), δ7.50-7.70 (5H, m), δ9.95 (1H, s), δ10.95 (1H, s)

[0539] MS (APCI−ve): [M]⁻, at m/z 402/404 (C₂₃H₁₅ClN₂O₃ requires [M]⁻,at m/z 402/404)

EXAMPLE 3

[0540]3-(3-Bromo-4-methylphenylamino)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione

[0541] A mixture of 3-bromo-4-methylaniline (0.220 g, 1.18 mmol),3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (0.100 g, 0.40 mmol) and1-methyl-2-pyrrolidinone (1.0 mL) was heated in an oil bath at 200° C.for 51 minutes. The mixture was diluted with aqueous hydrochloric acid(5 mL) and extracted with ethyl acetate (5 mL). The combined organicsolutions were evaporated and the residue chromatographed on silica gelusing dichloromethane as eluent to afford the title compound, a solid,following trituration with dichloromethane-hexane (90:10 v/v).

[0542]¹H NMR (CDCl₃): δ2.24 (3H, s), δ6.65-7.70 (7H, m, reduces to 5H onD₂O Exchange) and δ8.05 (2H, m).

[0543] MS (APCI−ve): [M−H]⁻ at m/z 400/402 (C₁₇H₁₂BrN₃O₄ requires [M−H]⁻at m/z 400/402).

EXAMPLE 4

[0544] 3-(4-Methylphenylamino)-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione

[0545] A mixture of 3-hydroxy-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione(103 mg, 0.5 mmol) and 4-methylaniline (59 mg, 0.55 mmol) in1-methyl-2-pyrrolidinone (1 mL) was heated in a sealed tube at 150° C.for 24 hours. The reaction mixture was dissolved in ethyl acetate(20 mL)and washed with 1N HCl (2×20 mL), water (3×20 mL) and brine (20 mL). Thesolution was dried over magnesium sulphate, evaporated and the residuechromatographed on silica gel using dichloromethane-diethyl ether(gradient from 100:0 to 90:10 v/v) as eluent to afford the titlecompound as a solid.

[0546]¹H NMR (DMSO-d₆): δ2.35 (3H, s), δ6.50 (2H, d), δ6.64 (2H, d),δ6.77 (2H, d), δ6.90 (2H, d), δ9.26 (1H, br), δ9.44 (1H, br), δ10.64(1H, br).

[0547] MS (APCI+ve): [M+H]⁺ at m/z 295 (C₁₇H₁₄N₂O₃ requires [M+H]⁺ atm/z 295).

EXAMPLE 5

[0548] 3-(N-Methyl-N-phenylamino)-4-(indol-3-yl)-1H-pyrrole-2,5-dione.

[0549] A mixture of3-(N-methyl-N-phenylamino)-4-(indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione(Table B, Example B1; 2.00 g, 0.006 mol), aqueous potassium hydroxidesolution (10% w/v, 2 L). ethanol (50 mL) and n-butanol (200 mL) washeated at reflux for 5 hours. The cooled reaction mixture was filteredand the filtrate acidified to pH 1 by addition of conc, hydrochloricacid. The mixture was cooled to 0° C. and the resulting solid filtered,washed with water and recrystallized from acetonitrile to give thecorresponding maleic anhydride. This anhydride (0.4 g. 1.25 mmol) wassuspended in a mixture of concentrated aqueous ammonium hydroxide andDMF and heated in stainless steel bomb at 130° C. for 4 hours. Theresulting mixture was diluted with water and extracted withdichloromethane and the dried organic solution evaporated to give asolid. This was chromatographed on silica gel using a gradient of 0-5%(v/v) of methanol in dichloromethane as eluent to afford the titlecompound, a solid.

[0550]¹H NMR (DMSO-d₆): δ3.07 (3H, s), δ6.75-7.45 (9H, m), δ7.68 (1H,s), δ10.70 (1H, br) and δ11.70 (1H, br).

[0551] MS (APCI+ve): [M+H]⁺ at m/z 318 (C₁₉H₁₅N₃O₂ requires [M+H]⁺ atm/z 318).

[0552] Further elution of the chromatography column afforded3-amino-4-(indol-3-yl)-1H-pyrrole-2,5-dione (Table B, Example B2) as abyproduct.

EXAMPLE 6

[0553] 3-(Indan-5-ylamino)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione

[0554] 3-(Indan-5-ylamino)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (TableA, Example A359; 0.3 g, 0.9 mmol) and 10% Pd/C (60 mg) in ethanol (25mL) was hydrogenated at atmospheric temperature and pressure for 2hours. The reaction mixture was filtered through Kieselguhr and thefiltrate concentrated in vacuo to give an orange solid. The crudeproduct was taken up in dichloromethane (10 mL) and treated withdi-tert-butyl dicarbonate (0.216 g, 1 mmol) and the mixture stirred atambient temperature for 18 hours. The reaction mixture was poured intosaturated aqueous sodium bicarbonate (10 mL) and extracted intodichloromethane (3×10 mL). The combined organics were washed with brine,dried over anhydrous sodium sulfate and concentrated in vacuo.Chromatography on silica gel using dichloromethane-methanol gave theproduct amine as an orange powder.

[0555]¹H NMR (DMSO-d₆): δ1.85 (2H, quintet), δ2.50 (2H, t), δ2.66 (2H,t), δ4.82 (2H, s), δ5.89 (1H, d), δ6.36 (2H, m), δ6.47 (1H, s), δ86.25(2H, m), δ6.85 (1H, d), δ9.13 (1H, br) and δ10.58 (1H, br).

[0556] MS (APCI+ve): [M+H]⁺ at m/z 320 (C₁₉H₁₇N₃O₂ requires [M+H]⁺ atm/z 320)

EXAMPLE 7

[0557] 3-(Indan-5-ylamino)-4-(3-acetylaminophenyl)-1H-pyrrole-2,5-dione

[0558] 3-(Indan-5-ylamino)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (TableA, Example A359; 0.3 g, 0.9 mmol) and 10% Pd/C (60 mg) in ethanol (25mL) was hydrogenated at atmospheric temperature and pressure for 2hours. The reaction mixture was filtered through Kieselguhr and thefiltrate concentrated in vacuo to give an orange solid. The crudeproduct was taken up in dichloromethane (5 mL) and treated with aceticanhydride (85 μL, 0.9 mmol) and stirred for 3 hours at ambienttemperature. The reaction mixture was poured onto saturated aqueoussodium bicarbonate solution (10 mL) and extracted into ethyl acetate(3×10 mL). The combined organics were washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. Chromatography onsilica gel using dichloromethane-methanol gave the desired compound asan orange powder.

[0559]¹H NMR (DMSO-d₆): δ1.83(2H, quintet), δ2.02 (3H, s), δ2.45 (2H,t), δ2.66 (2H, t), δ6.41 (2H, m), δ6.59 (1H, d), δ6.84 (2H. d), δ6.90(1H, t), δ7.38 (1H, d), δ9.30 (1H, bs), δ9.68 (1H, s) and δ10.61 (1H,bs)]

[0560] MS (APCI−ve): [M−H]⁻ at m/z 360 (C₂₁H₁₉N₃O₃ requires [M−H]⁻ atm/z 360).

EXAMPLE 8

[0561]3-(Indan-5-ylamino)-4-[3-[(3-fluorophenylaminocarbonyl)amino]phenyl]-1H-pyrrole-2,5-dione

[0562] 3-(Indan-5-ylamino)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (TableA, Example A599; 0.08 g, 0.3 mmol) in dichloromethane (10 mL) was wastreated with 3-fluorophenyl isocyanate (0.038 mg, 0.3 mmol). The mixturewas shaken on an orbital shaker for 72 hours. Saturated aqueous sodiumbicarbonate (5 mL) was added, shaking continued for 5 minutes and theorganic layer transferred directly onto a column of silica gel. Elutionwith dichloromethane gave the product as a yellow solid.

[0563]¹H NMR (DMSO-d₆): δ1.78 (2H, quintet), δ2,44 (2H, t), δ2.62 (2H,t), δ6.47 (2H, m), δ6.61 (1H, dd), δ6.83 (2H, m), δ6.93 (2H, m), δ7.09(1H, dd), δ7.28 (2H, m), δ7.45 (1H, dd), δ8.42 (1H, br), δ8.72 (1H, br),δ9.30 (1H, br) and δ10.65 (1H, br).

[0564] MS (APCI−ve) [M]⁻ at m/z 456 (C₂₆H₂₁FN₄O₃ requires [M]⁻ at m/z456).

EXAMPLE 9

[0565]3-(Indan-5-ylamino)-4-[3-(benzoylamino)phenyl]-1H-pyrrole-2,5-dione

[0566] 3-(5-Indan-5-ylamino)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione(Table A, Example A599; 0.100 g, 0.3 mmol) in dichloromethane (3 mL) wasadded to a solution of benzoic acid (0.042 g, 0.33 mmol),1-hydroxybenzotriazole (0.047 g, 0.33 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.063 g,0.33 mmol in dichloromethane (5 mL). The mixture was shaken on anorbital shaker for 72 hours. Saturated aqueous sodium bicarbonate (5 mL)was added, shaking continued for 5 minutes and the organic layertransferred directly onto a column of silica gel. Elution withdichloromethane gave the product as a yellow solid.

[0567]¹H NMR (DMSO-d₆): δ1.83 (2H, quintet), δ2,43 (2H, t), δ2.57 (2H,t), δ6.42 (1H, s), δ6.30 (2H, m), δ6.83 (1H, d), δ7.02 (1H, t), δ7.22(1H, s), δ7.56 (4H, m), δ7.86 (2H, dd), δ9.38 (1H, br), δ9.98 (1H, br)and δ10.68 (1H, bs).

[0568] MS (APCI−ve): [M−H]⁻ at m/z 422 (C₂₆H₂₁N₃O₃ requires [M−H]⁻ atm/z 422)

EXAMPLE 10

[0569]3-[4-(2-Aminoethyl)phenylamino]-4-(2-methoxyphenyl)-1H-pyrrole-2,5-dione

[0570] A solution of3-[4-[2-(t-butoxycarbonylamino)ethyl]phenylamino]-4-(2-methoxyphenyl)-1H-pyrrole-2,5-dione(0.060 g, 0.13 mmol) and trifluoroacetic acid (4 drops) in drv DCM (5mL) was stirred for 18 hours at room temperature. The suspension wasdiluted with ethyl acetate (10 mL), poured onto sodium bicarbonate (20mL) and extracted with ethyl acetate (3×10 mL). The combined organicsolutions were washed with brine, dried with magnesium sulfate,evaporated and the residue triturated with a mixture ofhexane-dichloromethane (95:5 v/v) to afford the title compound as anorange solid.

[0571]¹H NMR (CDCl₃), δ1.52 (2H, br), δ2.59 (2H, t), δ2.83 (2H, t),δ3.16 (3H, s), δ6.44 (1H, d), δ6.58 (2H, d), δ6.79 (2H,d), δ6.97-6.93(1H, m), δ7.22-7.17 (3H, m) and δ7.33 (1H, d).

[0572] MS (APCI+ve): [M+H]⁺ at m/z 338 (C₁₉H₁₉N₃O₃ requires [M+H]⁺ at338).

EXAMPLE 11

[0573]3-(3-Fluoro-4-methylphenylamino)-4-[4-(methoxycarbonyl)phenyl]-1H-pyrrole-2,5-dione

[0574] A mixture of3-(3-Fluoro-4-methylphenyl-amino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione(Example A705, 126 mg, 0.3 mmol), tetrakis(triphenylphosphine)-palladium(0) (35 mg, 0.03 mmol) and methanol (10 mL) wasplaced in a 50 mL two necked round bottomed flask. One arm of the flaskwas sealed with a septum and to the other arm was fitted a refluxcondenser, topped with a multiway tap connected respectively to vacuum,a carbon monoxide cylinder and to a balloon. Using the multiway tap, theflask was alternately evacuated and flushed with carbon monoxide, andthe process repeated several times to unsure an atmosphere of carbonmonoxide within the flask. The balloon was charged with carbon monoxideand this was then opened to the reaction flask for the duration of thereaction in order to maintain a slight positive pressure of carbonmonoxide within the flask. Triethylamine (100 uL, 0.7 mmol) was addedand the mixture heated at reflux for 16 hours. The mixture was cooledand diluted with ethyl acetate and the resulting solution washed withaqueous hydrochloric acid (1M, 50 mL), water (50 mL) and brine (50 mL).The organic solution was dried over magnesium sulphate and evaporated toafford a solid. This was chromatographed on silica gel usingdichloromethane-ether (98:2 v/v) as eluent to afford the title compound,a solid.

[0575]¹H NMR (CDCl₃): δ2.14 (3H, s), δ3.90 (3H, s), δ6.35-7.30 (7H, m)and δ7.82 (2H, m),

[0576] MS (APCI+ve): [M+H]⁺ at m/z 355 (C₁₉H₁₅FN₂O₄ requires [M+H]⁺ at355).

EXAMPLE 12

[0577]3-[4-[2-[N-[6-(Acetylamino)hexyl]aminocarbonyl]ethyl]phenylamino]-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione

[0578] A solution of triethylamine (81 mg, 0.8 mmol) in dry N,N-dimethylformamide (5 mL) was added to a mixture of3-[4-[2-(hydroxycarbonyl)ethyl]phenylamino]-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione(Example A763, 152 mg, 0.4 mmol), N-(6-aminohexyl)acetamidehydrochloride (78 mg, 0.4 mmol),1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.4mmol) and 1-hydroxybenzotriazole (54 mg, 0.4 mmol) and the resultingmixture stirred at room temperature for 18 hours. The mixture wasdiluted with ethyl acetate (25 mL) and washed successively with water(2×25 mL). saturated aqueous sodium bicarbonate solution (25 mL), water(2×25 mL), brine (25 mL), dried over magnesium sulphate andconcentrated. The residue was redissolved in dichloromethane-methanol(1:1 v/v), filtered and evaporated to afford the title compound as afoam.

[0579]¹H NMR (DMSO-d₆); δ1.10-1.40 (8H, m), δ1.77 (3H, s), δ2.15 (2H,m), δ2.55 (2H, m), δ3.00 (4H, m), δ6.62 (2H, d), δ6.77 (2H, d),δ7.20-7.90 (6H, m), δ9.80 (1H, br) and δ10.85 (1H, br).

[0580] MS (APCI+ve): [M+H]⁺ at m/z 522 (C₂₇H₃₁N₅O₆ requires [M+H]⁺ at522).

EXAMPLE 13

[0581]3-[4-(trans-2-carboxyethenyl)phenylamino]-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione

[0582] A mixture of trans-4-aminocinnamic acid (0.205 g, 1.26 mmol),3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (0.123 g, 0.51 mmol)and 1-methyl-2-pyrrolidinone (1.0 mL) was heated in a sealed tube in ahotblock set at 69° C. for 28.5 hours. The mixture was diluted withaqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2×20mL). The combined organics were washed with brine (2×10 mL). dried overanhydrous magnesium sulphate and evaporated to dryness. The residue wastriturated with a mixture of dichloromethaie and ethyl acetate to affordthe title compound as a solid.

[0583]¹H NMR (DMSO-d₆): δ6.35 (1H, d), 6.74 (2H, d), 6.99 (2H, d),7.19(2H, d), 7.35 (2H, d), 7.42 (1H, d), 9.76 (1H, br), 10.89(1H, br)and δ12.23 (1H, br).

[0584] MS (APCI+ve): [M+H]⁺ at m/z 369/371 (C₁₉H₁₃N₂O₄ requires [M+H]⁺at m/z 369/371).

EXAMPLE 14

[0585]3-[4-(trans-2-carbamoylthenyl)phenylamino]-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione

[0586]3-[4-[trans-2-(ethoxycarbonyl)ethenyl]phenylamino)-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione(50 mg, 0.126 mmol) was dissolved in 2N methanolic ammonia (5 ml) andallowed to stand at room temp for 12 days. Aqueous ammonia (d 0.88, 5ml) was added and the solution stood at room temp for a further 8 days.The mixture was evaporated to dryness and the residue triturated withmethanol then ether to give the title compound as a solid.

[0587]¹H NMR (DMSO-d₆): δ10.75(1H, br), δ9.7 (1H, br), δ7.44 (1H, br),δ7.2 (5H, m), δ7.2 (3H, m), δ6.74 (2H, d), δ6.41 (1H, d).

[0588] MS (APCI+ve): [M+H]⁺ at m/z 368/370 (C₁₉H₁₄ClN₃O₃ requires [M+H]⁺at m/z 368/370).

EXAMPLE 15

[0589] 3-(Indol-1-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione

[0590] Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol)was added to a solution of indole (88 mg, 0.75 mmol) in THF (2 mL) atroom temperature. The mixture was stirred for 30 minutes prior to theaddition of a solution of1-(tert-butyldimethylsilyl)-3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione(Procedure method 1, 180 mg, 0.5 mmol) in THF (1 mL). The mixture wasstirred for 45 minutes then diluted with ethyl acetate (80 mL), washedwith dilute hydrochloric acid (20 mL), dried (MgSO₄) and concentrated.The residue was chromatographed on silica gel using a gradient ofhexane-ethyl acetate to afford the title compound, a solid.

[0591]¹H NMR (CD₃OD); δ6.42 (1H, d), 6.77 (1H, d), 6.82 (1H, t),7.00-7.60 (5H, m) and 8.05-8.25 (2H, m).

[0592] MS (APCI+ve): [M+H]⁺ at m/z 334 (C₁₈H₁₁N₃O₄ requires [M+H]⁺ at334).

EXAMPLE 16

[0593] 3-Amino-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione

[0594] 3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (1.0 g, 4 mmol)was suspended in a mixture of ethanol (20 mL) and aqueous 880 ammonia (5mL) and the mixture heated to 80° C. whilst ammonia gas was bubbledthrough the mixture for 4 hours. The mixture was cooled and concentratedand the residue chromatographed on silica gel using hexane-ethyl acetate(gradient from 1:1 v/v) as eluent to afford the title compound as asolid.

[0595]¹H NMR (CD₃COCD₃); δ6.77 (2H, br), 7.60 (1H, t), 8.04 (2H, m),8.50 (1H, t) and 9.33 (1H, br).

[0596] MS (APCI+ve): [M+H]⁺ at m/z 234 (C₁₀H₇N₃O₄ requires [M+H]⁺ at234).

EXAMPLE 17

[0597]3-[4-[2-methoxyethylaminocarbonylmethylthio]phenylamino]-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione

[0598] A solution of 2-methoxyethylamine in THF (0.32M, 1 mL) was addedto a mixture of3-[4-(carboxymethylthio)phenylamino]-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione(Example A941, 117 mg, 0.3 mmol),1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (57 mg, 0.3mmol) and 1-hydroxybenzotriazole (40 mg, 0.3 mmol) in dry THF (1 mL).The resulting solution was stirred at room temperature for 57 hours,then diluted with ethyl acetate (50 mL) and washed with dilutehydrochloric acid (1M, 50 ml), water (50 mL) and brine (50 mL), driedover magnesium sulphate and evaporated. The resulting gum waschromatographed on silica gel using dichloromethane-methanol (98:2 v/v)as eluent to afford the title compound, a solid.

[0599]¹H NMR (DMSO-d₆) d 3.20 (3H, s), 3.21 (2H, m), 3.25 (2H, t), 3,50(2H, s), 6.60-7.20 (8H, m), 8.10 (1H, t, exchanges with D₂O), 9.65 (1H,br, exchanges with D₂O) and 10.82 (1H, br, exchanges with D₂O).

[0600] MS (APCI+ve) [M+H]⁺ at m/z 446/448, C₂₁H₂₀ClN₃O₄S requires [M+H]⁺at m/z 446/448.

EXAMPLE 18

[0601] 3-(2-Methoxyethylamino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione

[0602] A solution of3-(3-fluoro-4-methylphenylamino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione(Example A705, 126 mg, 0.3 mmol) and 2-methoxyethylamine (0.2 mL, 2,3mmol) in DMF (2 mL) was stirred at room temperature for 113 hours thendiluted with hydrochloric acid (0.5M, 50 mL) and extracted with ethylacetate (50 mL). The ethyl acetate solution was washed with water (2×50mL) and brine (50 mL), dried over magnesium sulphate and evaporated. Theresidue was chromatographed on silica gel using dichloromethane-diethylether (99:1 v/v) as eluent to afford the title compound, a solid.

[0603]¹H NMR (CDCl₃): 3.25 (2H, m), 3.35 (3H, s), 3.40 (2H, t), 5.67(1H, br, exchanges with D₂O), 6.95 (1H, br, exchanges with D₂O), 7.05(2H, d) and 7.70 (2H, d).

[0604] MS (APCI+ve) [M+H]⁺ at m/z 373, C₁₃H₁₃IN₂O₃ requires [M+H]⁺ atm/z 373.

EXAMPLE 19

[0605] 3-Amino-1-[4-(4-chlorophenyl)-2,5-dioxo-1H-pyrrol-3-yi]pyridiniumchloride

[0606] A mixture of 3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione(100 mg, 0.41 mmol) and 3-aminopyridine (42.7 mg, 0.45 mmol) in dry THF(2,5 mL) was heated at 50° C. for 2 hours then stirred at roomtemperature overnight. The resulting suspension was filtered and thesolid washed with dichloromethane (20 mL), then hexane (10 mL) to givethe title compound as a solid.

[0607]¹H NMR (DMSO): δ7.07 (2H,br), δ7.43 (2H,d), δ7.61 (2H,d),δ7.93-7.81 (2H,m), δ8.10-8.07 (2H,m) and δ12.07 (1H,br).

[0608] MS (APCI+ve): [M+H]⁺ at m/z 301/303 (C₁₅H₁₁N₃O₂Cl requires [M+H]⁺at m/z 301/303)

EXAMPLE 20

[0609]3-[5-methoxy-6-[4-ethylpiperazin-1-yl]-indolin-1-yl]-4-[3-fuorophenyl]-1H-pyrrole-2,5-dione

[0610] A solution of 3-chro-4-(3-fluorophenyl)-1H-pyrrole-2,5-dione (100mg, 0.44 mmol.), 5-methoxy-6-[4-ethylpiperazin-1-yl]-indoline (156 mg,0.44 mmol.) and triethylamine (0.12 mL, 0.88 mmol.) in dry1-methylpyrrolidin-2-one (2 mL) was heated under argon at 65 C. for 36h. The mixture was allowed to stand overnight at RT then diluted withwater (80 mL) and extracted with ethyl acetate (3×60 mL). The combinedorganic solutions were washed with water (2×60 mL), brine, dried withmagnesium sulphate, evaporated and the residue triturated with a mixtureof dichloromethane and hexane to afford the title compound as a solid.

[0611]¹H NMR (DMSO-d₆): δ10.80 (1H, br), δ7.23-7.17 (1H, m), δ7.00 (1H,t), δ6.92-6.85 (3H, m), δ5.44 (1H, s), δ4.42 (2H, t), δ3.71 (3H, s),δ3.12 (2H, t), δ2.29 (10H, br,s), δ0.96 (3H, t)

[0612] MS (APCI+ve): [M+H]⁺ at m/z 451 (C₂₅H₂₇N₄O₃F requires [M+H]⁺ atm/z 451)

EXAMPLE 21

[0613]3-[2-(Hydroxymethyl)indolin-1-yl]-4-(3-nitrophenyl)-1H-pyrrole-2,5-dionesingle enantiomer

[0614] A solution of racemic3-[2-(Hydroxymethyl)indolin-1-yl]-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione(Example D102, 30 mg) in acetone (1 ml) was separated into it's twoenantiomers by repeated high pressure liquid chromatography of aliquotsof the solution. The chromatography was performed on a waters 6000instrument equipped with a 10 mm chiracel AD column using hexane-ethanol(85:15 v/v) as eluent at 5 ml min⁻¹. The solvent was removed at reducedpressure to give the separated enantiomers as solids. Enantiomer 1 (12mg, 100% chiral purity), enantiomer 2 (11 mg, 96% chiral purity).

[0615]¹H NMR (MeOH): δ2.07-2.25 (2H,m), 2,48 (1H,dd), 2.65 (1H,dd), 4.10(1H,hept), 4.45 (1H,d), 5.33 (1H,t), 5.52 (1H,t), 5.95 (1H, d), 6.16(1H,t), 6.42 (1H, d), 6.78 (1H,dd), 6.85 (1H, d).

[0616] MS (APCI+ve) [M+H]⁺ at m/z 366, (C₁₉H₁₅IN₃O₅ requires [M+H]⁺ atm/z 366).

EXAMPLE 22

[0617]3-(3,5-Di-fluorophenylamino)-4-(2,3-di-fluorophenyl)-1H-pyrrole-2,5-dione

[0618] A solution of 3,5-difluoroaniline (161 mg, 0.00125 mol) and3-chloro-4-(2,3-di-fluorophenyl)-1H-pyrrole-2,5-dione (122 mg, 0.0005mol) in methanol (2 mL) was heated in a sealed tube at 65° C. for 8days. The mixture was acidified with aqueous hydrochloric acid (1M) andextracted with ethyl acetate. The combined organic solutions were washedwith water and brine, dried with magnesium sulphate, evaporated and theresidue triturated with hexane-dichloromethane (95:5 v/v) to afford thetitle compound as a solid.

[0619]¹H NMR (DMSO-d₆): δ6.40 (2H, m), δ6.75 (1H, m), δ7.00-7.40 (3H,m), δ10.00 (1H, br) and δ11.00 (1H, br).

[0620] MS (APCI+ve): [M+H]⁺ at m/z 337 (C₁₆H₈F₄N₂O₂ requires M+H]⁺ atm/z 337).

[0621] Procedure Method 1

[0622]1-(tert-Butyldimethylsilyl)-3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione

[0623] Triethylamine (1.1 mL, 8 mmol) was added to a stirred suspensionof tert-butylchlorodimethylsilane (0.66 g, 4.4 mmol) and3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (1.0 g, 4 mmol) indichloromethane (15 mL) at room temperature. The mixture was stirredovernight then chromatographed directly on silica gel using ahexane-acetone gradient to afford the title compound.

[0624]¹H NMR (CDCl₃), δ0.51 (6H, s), 0.98 (9H, s), 7.70 (1H, t), 8.27(2H, m) and 8.80 (1H, m).

[0625] MS (APCI−ve): [M−H]⁻ at m/z 366/368 (C₁₆H₁₉ClN₂O₄Si requires[M−H]⁻ at 366/368).

[0626] The following additional procedures (Procedure Methods 2 & 3)serve to illustrate a typical preparation of a non commercial aniline,by a method analogous to that described in Synthesis 1994, 1413.:

[0627] Procedure Method 2

[0628] 3-[(4-Nitrophenyl)thiolbenzoic Acid

[0629] A suspension of potassium carbonate (18 g) in acetone (140 mL) atambient temperature was treated with 3-mercaptobenzoic acid (10 g, 64.4mmol, 1 eq) followed by 4-nitrofluorobenzene (18 g, 127.7 mmol, 2 eq).The resultant mixture was stirred for 18 h and then poured ontosaturated sodium bicarbonate and washed with ethyl acetate. The basicaqueous layer was acidified with 5N HCl and extracted into ethyl acetate(3×100 mL). The combined organics were dried with anhydrous sodiumsulphate and concentrated in vacuo to give the product as a solid.

[0630]¹H NMR (DMSO): δ7.35 (2H, d), 7.66 (1H, t), 7.81 (1H, m), 8.06(2H, m), 8.16 (2H, d), and 13.31 (1H, bs).

[0631] MS (APCI−ve): (M−H]⁻ at m/z 274 (C₁₃H₉NO₄S requires [M−H]⁻ at m/z274)

[0632] Procedure Method 3

[0633] 3-[(4-Aminophenyl)thiolbenzoic Acid

[0634] A mixture of 3-[(4-nitrophenyl)thio]benzoic acid (11.2 g, 40.7mmol) and 10% Pd/C (0.5 g) in ethanol (250 mL) was hydrogenated atatmospheric temperature and pressure for 24 h. The mixture was filteredthrough Celite and concentrated in vacuo to give the required aniline asa solid.

[0635]¹H NMR (DMSO): δ5.59 (2H, bs), 6.64 (2H, d), 7.28 (3H, m), 7.37(1H, t), 7.52 (1H, s), 7.65 (1H, d), and 12,32 (1H, bs),MS (APCI+ve):[M+H]⁺ at m/z 246 (C₁₃H₁₁NO₂S requires [M+H]⁺ at m/z 246).

[0636] The further examples described herein were prepared according tothe methods disclosed herein, with particular reference to Examples 1 to22 above. Examples 1 to 22 themselves are shown as examples A1, A2, A3,A424, B3, A599, F1, F2, F6, A702, A770, A772, A832, A833, D19, B25,A968, B28, I3, D36, D109 and A929 respectively in Tables A, B, D, F andI.

[0637] The following tables of examples illustrate the invention, but donot limit it in any way. TABLE A Encompassing compounds of generalformula (XXX-1), wherein group R² of formula (I) is a phenyl ring,optionally substituted by one or more substituents R¹⁰ and group R³ offormula (I) is a phenyl ring, optionally substituted by one or moresubstituents R¹¹ and substituents R, R¹, R¹⁰ and R¹¹ are listed in TABLEA. (XXX-1)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example [M = H]⁻ areSee No. R R¹ R¹⁰ R¹¹ are Indicated Example No. A1 H H 4-Cl 3-Br377/379/381 1 A2 H H 4-Cl 4-COPh 402/404 [M]− 2 A3 H H 3-NO2 3-Br-4-Me400/402 [M − H]− 3 A4 H H H H 265 1 A5 Me H H H 279 1 A6 H H H 4-OMe 2951 A7 H H H 4-Me 279 1 A8 H H H 4-Cl 299/301 1 A9 H H H 2-Me 277 [M − H]−1 A10 H H H 2-OMe 295 1 A11 H H H 4-OnBu 337 1 A12 H H H 4-nBu 321 1 A13Me H H 4-Cl 313/315 1 A14 Me H H 4-OMe 309 1 A15 Et H H H 293 1 A16 Et HH 4-Cl 327/329 1 A17 Et H H 4-OMe 323 1 A18 Ph H H H 341 1 A19 Ph H H4-Cl 375/377 1 A20 Ph H H 4-OMe 371 1 A21 CH2Ph H H H 355 1 A22 CH2Ph HH 4-Cl 389 1 A23 CH2Ph H H 4-OMe 385 1 A24 H H H 4-SMe 311 1 A25 H H H4-(1-Morpholinyl) 350 1 A26 H H H 3-SMe 311 1 A27 H H H 3-OPh 357 1 A28H H H 4-F 283 1 A29 H H 4-Cl 4-OMe 329/331 1 A30 H H 4-OMe 2-OMe 325 1A31 H H 4-OMe 4-OnBu 367 1 A32 H H 4-OMe 3-OPh 387 1 A33 H H 4-OMe 3-SMe341 1 A34 H H 4-OMe 4-F 313 1 A35 H H 4-OMe 4-SMe 341 1 A36 H H 4-OMe4-nBu 351 1 A37 H H 4-OMe H 295 1 A38 H H 4-OMe 4-Cl 329/331 1 A39 H H4-Cl 3-Cl 333/335/337 1 A40 H H 4-Cl 2-OMe 329/331 1 A41 H H 4-Cl 4-OnBu371/373 1 A42 H H 4-Cl 3-OPh 391/393 1 A43 H H 4-Cl 3-SMe 345/347 1 A44H H 4-Cl 4-CF3 367/369 1 A45 H H 4-Cl 4-F 317/319 1 A46 H H 4-Cl 4-SMe345/347 1 A47 H H 4-Cl 3-CF3 367/369 1 A48 H H 4-Cl 4-nBu 355/357 1 A49H H 4-Cl H 299/301 1 A50 H H 4-Cl 2-Me-4-Cl 347/349/351 1 A51 H H 4-Cl4-Cl 333/335/337 1 A52 H H 4-Cl 2-Me 313/315 1 A53 H H 4-Cl2,3-[(—CH═CH—)2] 349/351 1 A54 H H 2,3-[(—CH═CH—)2] 4-OnBu 387 1 A55 H H2,3-[(—CH═CH—)2] 4-F 331 [M − H]− 1 A56 H H 2,3-[(—CH═CH—)2] 4-SMe 361 1A57 H H 2,3-[(—CH═CH—)2] 4-nBu 371 1 A58 H H 2,3-[(—CH═CH—)2] H 315 1A59 H H 4-OMe 4-OMe 325 1 A60 H H 4-OMe 3-Cl 329/331 1 A61 H H 4-OMe2-Me 309 1 A62 H H 3,4,5-tri-OMe 4-OMe 385 1 A63 H H 3,4,5-tri-OMe H 3551 A64 H H H 3-Cl 299 1 A65 H H 4-CF3 2-Me 345 [M − H]− 1 A66 H H 4-CF32-Et 359 [M − H]− 1 A67 H H 4-CF3 2-iPr 375 1 A68 H H 4-CF3 2-F 349[M −H]− 1 A69 H H 4-CF3 2-Cl 365/367 [M − H]− 1 A70 H H 4-CF3 2-SMe 379 1A71 H H 4-CF3 3-SMe 379 1 A72 H H 4-CF3 3-Me 345 [M − H]− 1 A73 H H4-CF3 3-Et 361 1 A74 H H 4-CF3 3-OMe 363 1 A75 H H 4-CF3 3-Cl 365/367A76 H H 4-CF3 3-F 349 [M − H]− 1 A77 H H 4-CF3 3-Br 409/411 [M − H]− 1A78 H H 4-CF3 3-I 457 [M − H]− 1 A79 H H 4-CF3 3-OCH2Ph 439 1 A80 H H4-CF3 3-CONH2 375 [M]− 1 A81 H H 3,4,5-tri-OMe 4-Cl 389/391 1 A82 H H4-Cl 2-Et 327/329 1 A83 H H 4-Cl 2-iPr 341/343 1 A84 H H 4-Cl 2-F317/319 1 A85 H H 4-Cl 2-SMe 345/347 1 A86 H H 4-Cl 3-Me 313/315 1 A87 HH 4-Cl 3-Et 327/329 1 A88 H H 4-Cl 3-OMe 329/331 A89 H H 4-Cl 3-F315/317 [M − H]− 1 A90 H H 4-Cl 3-I 423/425 [M − H]− A91 H H 4-Cl3-OCH2Ph 405/407 1 A92 H H 4-Cl 3-CONH2 342/344 1 A93 H H 2-CF3 3-SMe377 [M − H]− 1 A94 H H 2-CF3 3-Me 347 1 A95 H H 2-CF3 3-Et 361 1 A96 H H4-OMe 4-Me 309 1 A97 H H 4-OMe 4-tBu 351 1 A98 H H 4-OMe 3,4-[(CH2)3]335 1 A99 H H 4-OMe 3,5-di-Me 323 1 A100 H H 4-OMe 3-OCH2Ph 401 1 A101 HH 4-OMe 3-OMe 325 1 A102 H H 4-OMe 3-1 421 1 A103 H H 4-OMe 3,4-[OCH2O]339 1 A104 H H 4-OMe 3,5-di-OMe 355 1 A105 H H 3-OMe 4-nBu 351 1 A106 HH 3-OMe 3-OPh 387 1 A107 HA107 H 3-OMe 4-SMe 341 1 A108 H H 3-OMe 4-Me309 1 A109 H H 3-OMe 4-iBu 351 1 A110 H H 3-OMe 3,5-di-Me 323 1 A111 H H3-OMe 3-OCH2Ph 401 1 A112 H H 3-OMe 3-OMe 325 1 A113 H H 3-OMe 3-I 421 1A114 H H 3-OMe 3,4-[OCH2O] 339 1 A115 H H 3-OMe 3,5-di-OMe 355 1 A116 HH 3-OMe 4-OMe 325 1 A117 H H 3-OMe 3,4-[(CH2)3] 335 1 A118 H H 3-OMe4-SCF3 395 1 A119 H H 2-OMe 4-nBu 351 1 A120 H H 2-OMe 3-OPh 387 1 A121H H 2-OMe 4-SMe 341 1 A122 H H 2-OMe 4-Me 309 1 A123 H H 2-OMe 4-tBu 3511 A124 H H 2-OMe 3,4-[(CH2)3] 335 1 A125 H H 2-OMe 3,5-di-Me 323 1 A126H H 2-OMe 3-OCH2Ph 401 1 A127 H H 2-OMe 3-OMe 325 1 A128 H H 2-OMe 3-I421 1 A129 H H 2-OMe 3,5-di-OMe 355 1 A130 H H 2-OMe 4-OMe 325 1 A131 HH 2-OMe 3-CF3 363 1 A132 H H 4-OMe 3-CF3 363 1 A133 HA133 H 3-OMe 3-CF3363 1 A134 H H 2-OMe 3,4-[OCH2O] 339 1 A135 H Me 4-CF3 H 347 1 A136 H H4-CF3 H 333 2 A137 H H 4-CF3 2,3-[(—CH═CH—)2] 383 2 A138 H H 4-CF3 4-CF3401 2 A139 H H 4-CF3 4-CN 358 2 A140 H H 4-CF3 4-COPh 437 2 A141 H H2-CF3 H 333 2 A142 H H 2-CF3 2-Me 347 2 A143 H H 4-CF3 2-Me-4-Cl 381/3832 A144 H H 4-OMe 3-CH2OH 325 1 A145 H H H 2,3-[(—CH═CH—)2] 315 1 A146 HH 4-Cl 3-OH 315/317 1 A147 H Me H H 279 1 A148 H Me 4-Ph H 355 1 A149 HMe 4-Cl H 313/315 1 A150 H Me 4-OMe H 309 1 A151 H Me 3-NO2 H 324 1 A152H Me 3-OMe H 309 1 A153 H H 4-CF3 4-CO2H 377 2 A154 H H 4-Ph 4-Me 355 1A155 H H 4-Ph 4-OnBu 412 [M]− A156 H H 4-Ph 4-nBu 397 1 A157 H H 4-Ph4-SMe 387 1 A158 H H 4-Ph 2-Me 355 1 A159 H H 4-Ph 3-SMe 387 1 A160 H H4-Ph 3-OPh 433 1 A161 H H 4-Ph 3-Cl 375/377 1 A162 H H 4-Ph 3-COMe 383 1A163 H H 4-Ph 3-Br 417/419[M − H]− 1 A164 H H 4-Ph 3-(5-Oxazolyl) 407[M]− 1 A165 H H 4-Ph 3-OH 357 1 A166 H H 3-NO2 4-Me 324 1 A167 H H 3-NO24-OnBu 382 1 A168 H H 3-NO2 4-SMe 356 1 A169 H H 3-NO2 2-Me 324 1 A170 HH 3-NO2 3-SMe 356 1 A171 H H 3-NO2 3-OPh 402 1 A172 H H 3-NO2 3-Cl344/346 1 A173 H H 3-NO2 3,5-di-Cl 376/378/380 [M − H]− 1 A174 H H 3-NO23-COMe 350 [M − H]− 1 A175 H H 3-NO2 3-Br 388/390 1 A176 H H 3-NO23-(5-Oxazolyl) 375 [M − H]− 1 A177 H H 3-NO2 3-OH 326 1 A178 H H 3-NO24-nBu 366 1 A179 H H 4-CF3 4-NO2 378 2 A180 H H 3,4,5-tri-OMe 4-Me 369 1A181 H H 3,4,5-tri-OMe 4-OnBu 427 1 A182 H H 3,4,5-tri-OMe 4-nBu 411 1A183 H H 3,4,5-tri-OMe 4-SMe 401 1 A184 H H 3,4,5-tri-OMe 3-SMe 401 1A185 H H 3,4,5-tri-OMe 3-COMe 397 1 A186 H H 3,4,5-tri-OMe3-(5-Oxazolyl) 422 1 A187 H H 3,4,5-tri-OMe 3-OH 371 1 A188 H H H 4-CF3333 1 A189 H H 4-OMe 4-(CH2)2OH 337 [M − H]− 1 A190 H H H 4-(CH2)2OH 3091 A19l H H 2-Cl 4-OMe 329 1 A192 H H H 3-CF3 331 [M − H]− 1 A193 H H4-Cl 4-CN 323/325 [M]− 2 A194 H H 4-CF3 2,4,6-tri-Me 375 2 A195 H H 4-Cl2,3-[(CH2)4] 353/355 1 A196 H H 4-Cl 4-tBu 355/357 1 A197 H H 4-Cl4-CH2P(O)(OEt)2 449/451 1 A198 H H 4-Cl 4-OPh 391/393 1 A199 H H 4-Cl4-(Cyclohexyl) 381/383 1 A200 H H 4-Cl 2-CH2Ph 389/391 1 A201 H H 4-Cl4-Br-3-Cl 411/413/415/417 1 A202 H H 4-Cl 4-I-3-Cl 459/461/463 1 A203 HH 4-Cl 3,4-di-Cl 367/369/371/373 1 A204 H H 4-Cl 3,5-di-Cl367/369/371/373 1 A205 H H 4-Cl 3,5-di-Cl-4-OH 383/385/387/389 1 A206 HH 4-Cl 3,5-di-F 335/337 1 A207 H H 4-Cl 4-Br 377/379/381 1 A208 H H 4-Cl4-I 425/427 1 A209 H H 4-Cl 3-NO2 344/346 1 A210 H H 4-Cl 2-OH 315/317 1A211 H H 4-Cl 4-OH 315/317 1 A212 H H 4-Cl 3,5-di-Br-4-Me469/471/473/475 1 A213 H H 4-Cl 3,4-[OCH2O] 343/345 1 A214 H H 4-Cl3,4-[CH═N—NH] 339/341 1 A215 H H 4-Cl 3,4-[NH—N═CH] 339/341 1 A216 H H4-Cl 3-Br-2-Me 391/393/395 1 A217 H H 4-Cl 3-Br-4-Me 391/393/395 1 A218H H 4-Cl 3-Cl-2-Me 347/349/351 1 A219 H H 4-Cl 3-F-4-Me 331/333 1 A220 HH 4-Cl 3-F-6-Me 331/333 1 A22l H H 4-Cl 4-Me 313/315 1 A222 H H 4-Cl2-CH2OH 329/331 1 A223 H H 4-Cl 3-CH2OH 329/331 1 A224 H H 4-Cl4-OH-2-Me 329/331 1 A225 H H 4-Cl 4-NHCOMe 356/358 1 A226 H H 4-Cl2,3-di-Me 327/329 1 A227 H H 4-Cl 2,4-di-Me 327/329 1 A228 H H 4-Cl3,4-di-Me 327/329 1 A229 H H 4-Cl 3,5-di-Me 327/329 1 A230 H H 4-Cl3-CH2OH-6-Me 343/345 1 A231 H H 4-Cl 4-OMe-2-Me 343/345 1 A232 H H 4-Cl4-(CH2)2OH 343/345 1 A233 H H 4-Cl 3,5-di-OMe 359/361 1 A234 H H 4-Cl4-CH2CN 338/340 1 A235 H H 4-Cl 3,4-[CH═CH—NH] 338/340 1 A236 H H 4-Cl3-COMe 341/343 1 A237 H H 4-Cl 4-CH2CO2H 357/359 1 A238 H H 4-Cl3,4-[(CH2)3] 337/339 [M − H]− 1 A239 H H 4-Cl 4-N(Me)COMe 370/372 1 A240H H 4-Cl 3-OiPr 357/359 1 A241 H H 4-Cl 4-(CH2)2CONH2 370/372 1 A242 H H3,4-[OCH2O] 3-OPh 401 1 A243 H H 4-Cl 4-CONH2 340/342 [M − H]− 3 A244 HH 4-F 2-Me 297 1 A245 H H 4-F 3-SMe 329 1 A246 H H 4-F 3-Cl 317/319 1A247 H H 4-F 4-Cl-2-Me 331/333 1 A248 H H 4-F 3-OPh 375 1 A249 H H 4-F4-SMe 329 1 A250 H H 4-F 4-tBu 339 1 A251 H H 4-F 3,4-[(CH2)3] 323 1A252 H H 2-OMe 3-Me 309 1 A253 H H 2-OMe 3-F 313 1 A254 H H 2-OMe 2-F313 1 A255 H H 2-OMe 4-Cl-2-Me 343/345 1 A256 H H 2-OMe 2-Me 309 1 A257H H 2-OMe 3-SMe 341 1 A258 H H 3-Cl 2-Me 313/315 1 A259 H H 3-Cl 3-SMe345/347 1 A260 H H 3-Cl 3-Cl 333/335/337 1 A261 H H 3-Cl 4-Cl-2-Me347/349/35 1 1 A262 H H 3-Cl 3-OPh 391/393 1 A263 H H 3-Cl 4-SMe 345/3471 A264 H H 3-Cl 4-tBu 355/357 1 A265 H H 3-Cl 3,4-[(CH2)3] 339/341 1A266 H H 3,4-[(—CH═CH—)2] 3-Me 329 1 A267 H H 3,4-[(—CH═CH—)2] 3-F 333 1A268 H H 3,4-[(—CH═CH—)2] 4-Cl-2-Me 363/365 1 A269 H H 3,4-[(—CH═CH—)2]2-Me 329 1 A270 H H 3,4-[(—CH═CH—)2] 3-SMe 361 1 A271 H H3,4-[(—CH═CH—)2] 3-Cl 349/351 1 A272 H H 4-I 2-Me 405 1 A273 H H 4-I3-SMe 437 1 A274 H H 4-I 3-Cl 425/427 1 A275 H H 4-I 4-Cl-2-Me 439/441 1A276 H H 4-I 3-OPh 483 1 A277 H H 4-I 4-SMe 437 1 A278 H H 4-I 4-tBu 4471 A279 H H 4-I 3,4-[(CH2)3] 431 1 A280 H H 4-OMe 3-Me 309 1 A281 H H4-OMe 3-F 313 1 A282 H H 3-OMe 2-Me 309 1 A283 H H 3-OMe 3-SMe 341 1A284 H H 3-OMe 3-Cl 329/331 1 A285 H H 2-OMe 3-Cl 329/331 1 A286 H H 4-F3-Br 361/363 1 A287 H H 4-OMe 3-Br 373/375 1 A288 H H 3,4-[(—CH═CH—)2]3-Br 393/395 1 A289 H H 4-I 3-Br 469/471 1 A290 H H 4-Cl 4-NO2 342/344[M − H]− 3 A291 H H 3,4-di-Cl 3-Br 411/413/415/417 1 A292 H H 3-Cl 3-Br377/379/381 1 A293 H H 2-Cl 3-OPh 391/393 3 A294 H H 2-Cl 3-Cl 333/335 3A295 H H 2-Cl 3-SMe 345/347 1 A296 H H 2-Cl 4-SMe 345/347 1 A297 H H3-OMe 4-CONH2 337 [M]− 3 A298 H H 4-Cl 4-CO2H 297/299 Fragment 3 ion[M-CO2H]− A299 H H 4-OMe 4-CN 320 3 A300 H H 2-Cl 4-nBu 355/357 1 A301 HH 2-Cl 3-Br 375/377/379 [M]− 1 A302 H H 2-Cl 4-Me 313/315 1 A303 H H4-Cl 3-Cl-6-Me 347/349/351 3 A304 H H 3-NO2 3-Cl-4-Me 356/358 [M − H]− 3A305 H H 3-NO2 4-COPh 414 3 A306 H H 3,5-di-F 3-Br 379/381 1 A307 H H3-CF3 3-Br 411/413 1 A308 H H 4-Me 3-Br 357/359 1 A309 H H 4-Br 3-SMe389/391 1 A310 H H 4-Br 4-Me 357/359 1 A311 H H 4-Br 3,5-di-Cl409/411/413/415 [M − H]− 1 A312 H H 4-Br 3-OPh 435/437 1 A313 H H 4-Br3,4-[(CH2)3] 383/385 1 A314 H H 4-Me 3-SMe 325 1 A315 H H 4-Me 4-Me 2931 A316 H H 4-Me 3-OPh 371 1 A317 H H 4-Me 3,4-[(CH2)3] 319 1 A318 H H4-Me 4-SMe 325 1 A319 H H 4-SMe 3-SMe 357 1 A320 H H 4-SMe 4-Me 325 1A321 H H 4-SMe 3-OPh 403 1 A322 H H 4-SMe 3,4-[(CH2)3] 351 1 A323 H H4-SMe 4-SMe 357 1 A324 H H 3-CF3 3-SMe 379 1 A325 H H 3-CF3 4-Me 347 1A326 H H 3-CF3 3,5-di-Cl 399/401/403 [M − H]− 1 A327 H H 3-CF3 3-OPh 4251 A328 H H 3-CF3 3,4-[(CH2)3] 373 1 A329 H H 3-CF3 4-SMe 379 1 A330 H H3,5-di-F 3-SMe 347 1 A331 H H 3,5-di-F 4-Me 315 1 A332 H H 3,5-di-F3,5-di-Cl 367/369/371 [M]− 1 A333 H H 3,5-di-F 3-OPh 393 1 A334 H H3,5-di-F 3,4-[(CH2)3] 341 1 A335 H H 3,5-di-F 4-SMe 347 1 A3J6 H H3,4-di-Cl 3-SMe 379/381/383 1 A337 H H 3,4-di-Cl 4-Me 347/349/351 1 A338H H 3,4-di-Cl 3,5-di-Cl 399/401/403/405/407 1 [M − H]− A339 H H3,4-di-Cl 3-OPh 423/425/427 [M]− 1 A340 H H 3,4-di-Cl 3,4-[(CH2)3]373/375/377 1 A341 H H 3,4-di-Cl 4-SMe 379/381/383 1 A342 H H 3-Br 3-SMe389/391 1 A343 H H 3-Br 4-Me 355/357 [M]− 1 A344 H H 3-Br 3,5-di-Cl409/411/413/415 [M − H]− 1 A345 H H 3-Br 3-OPh 435/437 1 A346 H H 3-Br3,4-[(CH2)3] 383/385 1 A347 H H 3-Br 4-SMe 389/391 1 A348 H H 4-NO23-SMe 356 1 A349 H H 4-NO2 4-Me 324 1 A350 H H 4-NO2 3,5-di-Cl376/378/380 [M − H]− 1 A351 H H 4-NO2 3-OPh 402 1 A352 H H 4-NO23,4-[(CH2)3] 350 1 A353 H H 4-NO2 4-SMe 356 1 A354 H H 4-Br 4-SMe389/391 1 A355 H H 3-NO2 4-NO2 353 [M]− 3 A356 H H 3-NO2 3,5-di-Cl-4-OH392/394/396 [M − H] 1 A357 H H 3-NO2 4-tBu 366 1 A358 H H 3-NO23,5-di-Br-4-OH 482/484/486 1 A359 H H 3-NO2 3,4-[(CH2)3] 350 1 A360 H H3-NO2 3-Br-4-OCF3 470/472[M − H]− 1 A361 H H 3-NO2 3-Br-5-CF3 454/456[M− H]− 1 A362 H H 3-NO2 4-CH2CN 349 1 A363 H H 3-NO2 4-(CH2)2CONH2 381 1A364 H H 3-NO2 3-F 326[M − H]− 1 A365 H H 3-NO2 3-F-4-Me 342 1 A366 H H3-NO2 4-Cl 342/344[M − H]− 1 A367 H H 3-NO2 4-OMe 340 1 A368 H H 3-NO23-Et 338 1 A369 H H 3-NO2 2-F 328 A370 H H 3-NO2 3,5-di-F 344[M − H]− 1A371 H H 3-NO2 3,4-[S—CH═N] 367 1 A372 H H 3-NO2 4-OPh 402 1 A373 H H3-NO2 4-trans-CH═CHCO2H 378[M − H]− 1 A374 H H 3-NO2 4-OCH2Ph 416 1 A375H H 3-NO2 3-CO(CH2)2CO2Me 422[M − H]− 1 A376 H H 3-NO2 3-NO2 353 [M]− 3A377 H H 3-NO2 4-CN 333 [M]− 3 A378 H H 4-Cl 4-OH-3-CO2H 359/361 1 A379H H 4-Cl 3-CO2H 341/343 [M − H]− 1 A380 H H 4-Cl 4-SCH2CO2Me 403/405 1A381 H H 4-Cl 4-OH-3-NO2 360/362 1 A382 H H 4-Cl 4-(CH2)2CO2H 371/373 1A383 H H 4-Cl 4-Cl-3-CO2H 375/377/379 [M − H] 1 A384 H H 4-Cl4-(CH2)3CO2H 385/387 1 A385 H H 4-Cl 3-SO2CF3 429/431[M − H]− 1 A386 H H4-Cl 3-COPh 403/405 1 A387 H H 4-Cl 3,5-di-Br-4-OH 471/473/475/477 1A388 H H 4-Cl 4-CPh3 541/543 1 A389 H H 4-Cl 3-CH2CO2H 355/357 [M − H]−1 A390 H H 4-Cl 4-(1-Adamantyl) 433/435 1 A391 H H 4-Cl 3-CO2H-4-[S-(2-373/375 Fragment 1 CO2H-Ph)] ion [M-C7H5O2]− A392 H H 4-Cl2-[O(CH2)2OMe]-5- 443/445 [M − H]− 1 (CH2)2CO2H A393 H H 4-Cl 3-Br-4-Cl411/413/415/417 1 A394 H H 4-Cl 2-OPh 391/393 1 A395 H H 4-Cl4-CH2SO2NHMe 311/313 Fragment 1 ion [M- CH4NO2S]+ A396 H H 3-NO2 4-CO2H352 [M − H]− 3 A397 H H 3-NO2 3-COPh 414 3 A398 H H 4-Cl 3-CH2CO2Me371/373 1 A399 H H 4-OH 3-Br 359/361 4 A400 H H 4-Br 4-COPh 447/449 3A401 H H 4-SMe 4-COPh 415 3 A402 H H 4-OH 4-SMe 327 4 A403 H H 4-iPr3-SMe 351[M − H]− 1 A404 H H 4-iPr 4-Me 319[M − H]− 1 A405 H H 4-iPr3,4-[(CH2)3] 345[M − H]− 1 A406 H H 3,5-di-Me 3-SMe 337[M − H]− 1 A407 HH 3,5-di-Me 4-Me 305[M − H]− 1 A408 H H 3,5-di-Me 3,4-[(CH2)3] 331[M −H]− 1 A409 H H 3,5-di-Me 4-SMe 337[M − H]− 1 A410 H H 4-iPr 4-SMe 351[M− H]− 1 A411 H H 2-Br 3-SMe 387/389[M − H]− 1 A412 H H 2-Br 4-Me355/357[M − H]− 1 A413 H H 2-Br 3,4-[(CH2)3] 381/383[M − H]− 1 A414 H H2-Br 4-SMe 387/389[M − H]− 1 A415 H H 3,5-bis-CF3 3-SMe 446[M]− 1 A416 HH 3,5-bis-CF3 4-Me 414[M]− 1 A417 H H 3,5-bis-CF3 3,5-di-Cl 468/470/472[M]− 1 A418 H H 3,5-bis-CF3 3,4-[(CH2)3] 440[M]− 1 A419 H H 3,5-bis-CF34-SMe 446[M]− 1 A420 H H 4-OPh 3-SMe 401 [M − H]− 1 A421 H H 4-OPh 4-Me369[M]− 1 A422 H H 4-OPh 3,4-[(CH2)3] 395[M − H]− 1 A423 H H 4-OPh 4-SMe401[M − H]− 1 A424 H H 4-OH 4-Me 295 4 A425 H H 4-OCH2Ph 3-SMe 415[M −H]− 1 A426 H H 4-OCH2Ph 3,4-[(CH2)3] 409[M − H]− 1 A427 H H 4-OCH2Ph4-SMe 415[M − H]− 1 A428 H H 3,4-di-OMe 3-SMe 371 1 A429 H H 3,4-di-OMe4-Me 337[M − H]− 1 A430 H H 3,4-di-OMe 3,4-[(CH2)3] 363[M − H]− 1 A431 HH 3-Cl-4-OMe 4-SMe 373/375 [M − H]− 1 A432 H H 3-Cl-4-OMe 3-SMe 373/375[M − H]− 1 A433 H H 3-Cl-4-OMe 4-Me 341/343 [M − H]− 1 A434 H H3-Cl-4-OMe 3,4-[(CH2)3] 369/371 1 A435 H H 3-NO2 4-COMe 352 3 A436 H H4-OH 3-OPh 371[M − H]− 4 A437 H H 4-OH 3-Br-4-Me 371/373[M − H]− 4 A438H H 4-OH 3,4-[(CH2)3] 321 4 A439 H H 3,5-di-Me 3-OPh 383[M − H]− 1 A440H H 2-Br 3-OPh 434[M − H]− 1 A441 H H 3,5-bis-CF3 3-OPh 492[M]− 1 A442 HH 4-OCH2Ph 3-OPh 461[M − H]− 1 A443 H H 3-Cl-4-OMe 3-OPh 419/421 [M −H]− 1 A444 H H 3,4-di-OMe 3-OPh 415[M − H]− 1 A445 H H 4-OPh 3-OPh 447[M− H]− 1 A446 H H 4-OCH2Ph 4-Me 383[M − H]− 1 A447 H H 2-Cl 3-Cl-4-Me347/349/351 3 A448 H H 3,4-[OCH2O] 3-SMe 353[M − H]− 1 A449 H H3,4-[OCH2O] 4-Me 323 1 A450 H H 3,4-[OCH2O] 3,4-[(CH2)3] 349 1 A451 H H3,4-[OCH2O] 4-SMe 355 1 A452 H H 3,4-[OCH2O] 3-Br 387/389 1 A453 H H3,4-[OCH2O] 3-Br-4-Me 401/403 1 A454 H H 2-Me 4-Me 293 1 A455 H H 2-Me3,4-[(CH2)3] 319 1 A456 H H 2-Me 4-SMe 325 1 A457 H H 3-Me 3-OPh 371 1A458 H H 3-Br 4-Cl 375/377/379 [M − H]− 1 A459 H H 4-iPr 3-OPh 397[M −H]− 1 A460 H H 4-CH2OMe 3-SMe 353[M − H]− 1 A461 H H 4-CH2OMe 4-Me 321[M− H]− 1 A462 H H 4-CH2OMe H 307[M − H]− 1 A463 H H 4-CH2OMe 3-OPh 399[M− H]− 1 A464 H H 4-CH2OMe 3,4-[(CH2)3] 347[M − H]− 1 A465 H H 4-CH2OMe4-SMe 353[M − H]− 1 A466 H H 4-CH2OMe 3-Br 385/387[M − H]− 1 A467 H H4-CH2OMe 3-Br-4-Me 399/401[M − H]− 1 A468 H H 2-Me 4-Cl 313/315 1 A469 HH 2,5-di-OMe 3-SMe 369[M − H]− 1 A470 H H 2,5-di-OMe 4-Me 337[M − H]− 1A471 H H 2,5-di-OMe H 323[M − H]− 1 A472 H H 2,5-di-OMe 3-OPh 415[M −H]− 1 A473 H H 2,5-di-OMe 3,4-[(CH2)3] 363 [M − H]− 1 A474 H H2,5-di-OMe 4-SMe 369[M − H]− 1 A475 H H 2,5-di-OMe 3-Br 401/403 [M − H]−1 A476 H H 2,5-di-OMe 3-Br-4-Me 415/417[M − H]− 1 A477 H H 4-OCF3 3-SMe393 [M − H] 1 A478 H H 4-OCF3 4-Me 361[M − H]− 1 A479 H H 4-OCF3 H 347[M− H]− 1 A480 H H 4-OCF3 3-OPh 439[M − H]− 1 A4S1 H H 4-OCF3 3,4-[(CH2)3]387[M − H]− 1 A482 H H 4-OCF3 3-Br 425/427[M − H]− 1 A483 H H 4-OCF33-Br-4-Me 439/441 [M − H]− 1 A484 H H 4-OCF3 4-SMe 393[M − H]− 1 A485 HH 3-SCF3 3-SMe 409[M − H]− 1 A486 H H 3-SCF3 4-Me 377[M − H]− 1 A487 H H3-SCF3 H 363[M − H]− 1 A488 H H 3-SCF3 3-OPh 455[M − H]− 1 A489 H H3-SCF3 3,4-[(CH2)3] 403[M − H]− 1 A490 H H 3-SCF3 4-SMe 409[M − H]− 1A491 H H 3-SCF3 3-Br 441/443[M − H]− 1 A492 H H 3-SCF3 3-Br-4-Me455/457[M − H]− 1 A493 H H 3-Cl 4-Cl 333/335/337 1 A494 H H 4-Cl3,4-[S—CH═N] 356/358 1 A495 H H 2-OMe 3,4-[S—CH═N] 352 1 A496 H H 4-OMe3,4-[S—CH═N] 352 1 A497 H H 4-Br 4-CH═CHCO2H 411/413 [M − H]− 1 A498 H H4-Br 4-CH(OMe)Me 401/403 1 A499 H H 2-Me 3-SMe 325 1 A500 H H 2-Me3-Br-4-Me 371/373 1 A501 H H 3-F 3-SMe 329 1 A502 H H 3-F 4-Me 297 1A503 H H 3-F 3,5-di-Cl 351/353/355 1 A504 H H 3-F 3-OPh 375 1 A505 H H3-F 3,4-[(CH2)3] 323 1 A506 H H 3-F 4-SMe 329 1 A507 H H 3-F 3-Br361/363 1 A508 H H 3-F 3-Br-4-Me 375/377 1 A509 H H 2,4-di-Cl 3-SMe379/381/383 1 A510 H H 2,4-di-Cl 4-Me 347/349/350 1 A511 H H 2,4-di-Cl3-OPh 425/427/429 1 A512 H H 2,4-di-Cl 3,4-[(CH2)3] 373/375/377 1 A513 HH 2,4-di-Cl 4-SMe 379/381/383 1 A514 H H 2,4-di-Cl 3-Br 411/413/415/4171 A515 H H 2,4-di-Cl 3-Br-4-Me 425/427/429/431 1 A516 H H 3-Me 3-SMe 3251 A517 H H 3-Me 4-Me 293 1 A518 H H 3-Me 3,4-[(CH2)3] 319 1 A519 H H3-Me 4-SMe 325 1 A520 H H 3-Me 3-Br 357/359 1 A521 H H 3-Me 3-Br-4-Me371/373 1 A522 H H 4-Cl-3-NO2 3-SMe 388/390[M − H]− 1 A523 H H4-Cl-3-NO2 4-Me 356/358[M − H]− 1 A524 H H 4-Cl-3-NO2 3,5-di-Cl410/412/414/416[M −H]− 1 A525 H H 4-Cl-3-NO2 3-OPh 434/436[M − H]− 1A526 H H 4-Cl-3-NO2 3,4-[(CH2)3] 384/386 1 A527 H H 4-Cl-3-NO2 4-SMe390/392 1 A528 H H 4-Cl-3-NO2 3-Br-4-Me 434/436/438[M − H]− 1 A529 H H4-OH 3,4-[S—CH═N] 338 4 A530 H H 4-SMe 3,4-[S—CH═N] 368 1 A531 H H 4-I3,4-[S—CH═N] 448 1 A532 H H 2-Cl 3,4-[S—CH═N] 356/358 1 A533 H H4-Cl-3-NO2 3-Br 420/422/424[M − H]− A534 H H 3-NO2 3-CH2OH 338[M − H]− 1A535 H H 3-NO2 3-CONH2 351[M − H]− 1 A536 H H 3-NO2 3-OCH2CO2Et 410[M −H]− 1 A537 H H 3-NO2 3,4-di-Me 336[M − H]− 1 A538 H H 3-NO2 3-CO2H 352[M− H]− 1 A539 H H 3-NO2 3,4-[OCH2O] 352[M − H]− 1 A540 H H 3-NO23-CH2CO2Me 380[M − H]− 1 A541 H H 3-NO2 3-OCH2CO2Me 396[M − H]− 1 A542 HH 4-Br 3-Cl-4-Me 391/393/395 1 A543 H H 4-Me 3-Cl-4-Me 327/329 1 A544 HH 4-SMe 3-Cl-4-Me 359/361 1 A545 H H 2-OMe 3-Cl-4-Me 343/345 1 A546 H H4-OMe 3-Cl-4-Me 343/345 1 A547 H H 2-Cl 3-Br-4-Me 391/393/395 1 A548 H H4-Br 3-Br-4-Me 435/437/439 1 A549 H H 4-Me 3-Br-4-Me 371/373 1 A550 H H4-SMe 3-Br-4-Me 403/405 1 A551 H H 2-OMe 3-Br-4-Me 387/389 1 A552 H H4-OMe 3-Br-4-Me 387/389 1 A553 H H 2-Cl H 299/301 1 A554 H H 4-Br H343/345 1 A555 H H 4-Me H 279 1 A556 H H 4-SMe H 311 1 A557 H H 2-OMe H295 1 A558 H H 3-NO2 3-Cl-4-OH 358/360 [M − H]− 1 A559 H H 3-NO23-Cl-4-OMe 374/376 1 A560 H H 3-NO2 3-F-4-OMe 358 1 A561 H H 3-NO23,5-di-Br 464/466/468 [M − H]− 1 A562 H H 3-NO2 3,5-di-Br-4-Me478/480/482 [M − H]− 1 A563 H H 3-NO2 3,5-di-Me 338 1 A564 H H 3-NO2 H310 1 A565 H H 2-Me 3-OPh 371 1 A566 H H 3-NO2 4-(CH2)2OH 352 [M − H]− 1A567 H H 3-NO2 4-CH2CO2H 366 [M − H]− 1 A568 H H 3-NO2 4-CH2P(O)(OEt)2460 1 A569 H H 3-NO2 4-CH2SO2NHMe 415 [M − H]− 1 A570 H H 3-NO24-SCH2CO2H 398 [M − H]− 1 A571 H H 3-NO2 4-OH 324 [M − H]− 1 A572 H H3-NO2 4-(CH2)3CO2H 394 [M − H]− 1 A573 H H 3-NO2 4-CH2CO2Me 380 [M − H]−1 A574 H H 3-NO2 4-SCH2CO2Me 412 [M − H]− 1 A575 H H 3-NO2 4-(CH2)3CO2Me410 1 A576 H H 3-NO2 3,4-[CH═N—NH] 350 1 A577 H H 3-NO2 3,4-[NH—N═CH]350 1 A578 H H 4-Me 3,4-[S—CH═N] 336 1 A579 H H 4-Br 3,4-[S—CH═N]400/402 1 A580 H H 3,5-di-F 3,4-[S—CH═N] 358 1 A581 H H 3-NO2 2-Ph 384[M − H]− 1 A582 H H 2-OMe 3-Et 323 1 A583 H H 2-OMe 3-OH 311 1 A584 H H2-OMe 3-Br 373/375 1 A585 H H 2-OMe 3-COMe 337 1 A586 H H 2-OMe 3-COPh399 1 A587 H H 2-OMe 3-F-4-Me 327 1 A588 H H 2-OMe 3,5-di-Br-4-OH467/469/471 1 A589 H H 2-OMe 4-CH2CN 334 1 A590 H H 2-OMe 4-(CH2)2CONH2366 1 A591 H H 2-OMe 4-Cl 329/321 1 A592 H H 2-OMe 4-OPh 387 1 A593 H H2-OMe 4-OCH2Ph 401 1 A594 H H 2-OMe 3-F-4-OMe 343 1 A595 H H 2-OMe3-Cl-4-OMe 357/359 [M − H]− 1 A596 H H 2-OMe 3-Cl-4-OH 345/347 1 A597 HH 2-OMe 4-Br-3-Cl 407/409/411 1 A598 H H 2-OMe 3-Br-4-OCF3 457/459 1A599 H H 3-NH2 3,4-[(CH2)3] 320 6 A600 H H 4-SMe 2-Ph 385 [M − H]− 1A601 H H 3-NO2 4-I 435 [M]− 1 A602 H H 2-OMe 3-NO2 340 1 A603 H H 2-OMe3,5-di-F 331 1 A604 H H 2-OMe 3-Br-5-CF3 441/443 1 A605 H H 2-OMe3,5-di-Cl-4-OH 379/381/383 1 A606 H H 2-OMe 4-trans-CH═CHCO2H 363 [M −H]− 1 A607 H H 3-OPh 4-Me 371 1 A608 H H 3-OPh 3-Br 433/435 [M − H] 1A609 H H 3-OPh 4-SMe 401 [M − H]− 1 A610 H H 3-OPh 3-OPh 447 [M − H]− 1A611 H H 3-OPh 3,4-[(CH2)3] 395 [M − H]− 1 A612 H H 3-OPh H 357 1 A613 HH 3-OPh 3-SMe 403 1 A614 H H 3-OPh 3-Br-4-Me 447/449 [M − H] 1 A615 H H4-OnBu 4-Me 349 [M − H] 1 A616 H H 4-OnBu 3-OPh 428 [M]− 1 A617 H H4-OnBu 3,4-[(CH2)3] 377 1 A618 H H 4-OnBu H 337 1 A619 H H 4-OnBu 3-SMe383 1 A620 H H 4-OnBu 3-Br-4-Me 427/429 [M − H]− 1 A621 H H 2,6-di-Cl4-Me 347/349/351 1 A622 H H 2,6-di-Cl H 331/333/335 [M − H]− 1 A623 H H2,6-di-Cl SMe 377/379/381 [M − H]− 1 A624 H H 4-SMe 3-Br 389/391 1 A625H H 4-SMe 3-Cl 345/347 1 A626 H H 3,5-di-F 3-NO2 344 [M − H]− 1 A627 H H2-Cl 3,4-di-Me 327/329 1 A628 H H 4-Br 3,4-di-Me 369/371 [M − H]− 1 A629H H 4-Br 3-Br 419/421/423 [M − H]− 1 A630 H H 4-Br 3-Cl 375/377/379 [M −H] 1 A631 H H 3-Br 3-NO2 386/388 [M − H]− 1 A632 H H 2-OMe 3,4-di-Me 3231 A633 H H 3-OMe 3,4-di-Me 323 1 A634 H H 3-OPh 3,4-di-Me 385 1 A635 H H4-SMe 3,4-di-Me 337 [M − H]− 1 A636 H H 3-OPh 4-Br 433/435 [M − H]− 1A637 H H 4-Me 3-Cl 313/315 1 A638 H H 2-OMe 4-(CH2)2NHCO2tBu 436 [M −H]− 1 A639 H H 3-NO2 2,3-[(CH2)4] 362 [M − H]− 1 A640 H H 3-Cl 3-NO2342/344 [M − H] 1 A641 H H 2-OMe 4-CH2NHCO2tBu 422 [M − H] 1 A642 H H4-OnBu 4-SMe 383 1 A643 H H 4-C(OMe)2Ph 3-Cl 417/419 Fragment 1 ion[M-OMe]+ A644 H H 4-COPh 3-Cl 403/405 1 A645 H H 3-NO2-4-OMe 3-Cl374/376 1 A646 H H 2-NO2 3-Cl 344/346 1 A647 H H 2,4-di-OMe 3-SMe 369[M− H]− 1 A648 H H 2,4-di-OMe 4-Me 337[M − H]− 1 A649 H H 2,4-di-OMe H323[M − H]− 1 A650 H H 2,4-di-OMe 3-OPh 415[M − H]− 1 A651 H H2,4-di-OMe 3,4-[(CH2)3] 363[M − H]− 1 A652 H H 2,4-di-OMe 4-SMe 369[M −H]− 1 A653 H H 2,4-di-OMe 3-Br 403/404 1 A654 H H 2,4-di-OMe 3-Br-4-Me415/417[M − H]− 1 A655 H H 3-NO2 3-Cl-4-SMe 388/390 [M − H]− 1 A656 H H2-OMe 3-Cl-4-SMe 373/375 [M − H]− 1 A657 H H 3-NO2 4-CH2NHBoc 437 [M −H]− 1 A658 H H 4-Br 4-NMe2 386/388 1 A659 H H 2-OMe 4-NMe2 338 1 A660 HH 3-NO2 4-NMe2 353 1 A661 H H 3-NO2 3-OMe 373/375 1 A662 H H 3-NO2 3-OMe340 1 A663 H H 4-Br 3,4-di-OMe 403/405 1 A664 H H 2-OMe 3,4-di-OMe 355 1A665 H H 3-NO2 3,4-di-OMe 370 1 A666 H H 4-SO2Me 3-Br-4-Me 433/435[M −H]− 1 A667 H H 4-SO2Me 3-Br 419/421[M − H]− 1 A668 H H 4-SO2Me 4-SMe388[M]− 1 A669 H H 4-SO2Me 3,4-[(CH2)3] 382[M]− 1 A670 H H 4-SO2Me 3-OPh434[M]− 1 A671 H H 4-SO2Me H 342[M]− 1 A672 H H 4-SO2Me 4-Me 356[M]− 1A673 H H 4-SO2Me 3-SMe 388[M]− 1 A674 H H 2-F 3-SMe 327[M − H]− 1 A675 HH 2-F 4-Me 295[M − H]− 1 A676 H H 2-F 3-OPh 373[M − H]− 1 A677 H H 2-F3,4-[(CH2)3] 321 [M − H]− 1 A678 H H 2-F 4-SMe 327[M − H]− 1 A679 H H2-F 3-Br 359/36l[M − H]− 1 A680 H H 2-F 3-Br-4-Me 373/375[M − H]− 1 A681H H 2,3-di-F 3-Br-4-Me 391/393[M − H]− 1 A682 H H 2,3-di-F 3-Br377/379[M − H]− 1 A683 H H 2,3-di-F 4-SMe 345[M − H]− 1 A684 H H2,3-di-F 3,4-[(CH2)3] 339[M − H]− 1 A685 H H 2,3-di-F 3-OPh 391[M − H]−1 A686 H H 2,3-di-F H 299[M − H]− 1 A687 H H 2,3-di-F 4-Me 313[M − H]− 1A6R8 H H 2,3-di-F 3-SMe 345[M − H]− 1 A689 H H 3-NO2 3,4-[N═N—NH] 351 1A690 H Me 3-NO2 2-Me 338 1 A691 H H 3-NO2 2-OH 326 1 A692 H H 3-NO23-CF3 376[M − H]− 1 A693 H H 3-NO2 3-OCH2Ph 414[M − H]− 1 A694 H H 3-NO23-CO2H-4-Cl 386[M − H]− 1 A695 H H 3-NO2 3-CO2Me 368 1 A696 H H 3-NO22-OMe 340 1 A697 H H 3-NO2 3-I 436 1 A698 H H 3-NO2 3-CO2Me-4-Cl 402/4041 A699 H H 3-NO2-4-OMe 3,4-[(CH2)3] 380 1 A700 H H 3-NO2-4-OMe 3-Br-4-Me432/434 1 A701 H H 3-NO2 4-(CH2)2NHBoc 451 [M − H]− 1 A702 H H 2-OMe4-(CH2)2NH2 338 10 A703 H H 2-F H 281[M − H]− 1 A704 H H 4-Br 4-CH2NHBoc470/472 [M − H]− 1 A705 H H 4-I 3-F-4-Me 421 [M − H]− 1 A706 H H2-OCH2Ph 3-Cl 405/407 1 A707 H H 2-Cl 3,5-di-Cl-4-OH 383/385/387/389 1A708 H H 2-Cl 3,5-di-Br-4-OH 471/473/475/477 1 A709 H H 2-Cl 3-CO2H-4-Cl377/379/381 1 A710 H H 2-Cl 3-CO2H 343/345 1 A711 H H 2-Cl 3-OH 315/3171 A712 H H 2-Cl 3,4-[OCH2O] 343/345 1 A713 H H 2-Cl 3,4-[(CH2)3] 339/3411 A714 H H H 3,5-di-Cl-4-OH 349/351/353 1 A715 H H H 3,5-di-Br-4-OH437/439/441 1 A716 H H H 3-CO2H-4-Cl 343/345 1 A717 H H H 3-CO2H 309 1A718 H H H 3-OH 281 1 A719 H H H 3,4-[OCH2O] 309 1 A720 H H H3,4-[(CH2)3] 305 1 A721 H H 3-NO2-4-OMe H 340 1 A722 H H 3-NO2-4-OMe4-SMe 386 1 A723 H H 4-Br 3,5-di-Cl-4-OH 427/429/431/433 1 A724 H H 4-Br3,5-di-Br-4-OH 515/517/519/521 1 A725 H H 4-Br 3-CO2H-4-Cl 419/421/423[M− H] 1 A726 H H 4-Br 3-CO2H 387/389 1 A727 H H 4-Br 3-OH 359/361 1 A728H H 4-Br 3,4-[OCH2O] 387/389 1 A729 H H 4-I 3,5-di-Cl-4-OH 475/477/479 1A730 H H 4-I 3,5-di-Br-4-OH 563/565/567 1 A731 H H 4-I 3-CO2H-4-Cl469/471 1 A732 H H 4-I 3-CO2H 435 1 A733 H H 4-I 3-OH 407 1 A734 H H 4-I3A-[OCH2O] 435 1 A735 H H 3-Me 3,5-di-Cl-4-OH 363/365/367 1 A736 H H3-Me 3,5-di-Br-4-OH 451/453/455 1 A737 H H 3-Me 3-CO2H-4-Cl 357/359 1A738 H H 3-Me 3-CO2H 323 1 A739 H H 3-Me 3-OH 295 1 A740 H H 3-Me3,4-[OCH2O] 323 1 A741 H H 3-F 3,5-di-Cl-4-OH 367/369/371 1 A742 H H 3-F3,5-di-Br-4-OH 455/457/459 1 A743 H H 3-F 3-CO2H-4-Cl 361/363 1 A744 H H3-F 3-CO2H 327 1 A745 H H 3-F 3-OH 299 1 A746 H H 3-F 3,4-[OCH2O] 327 1A747 H H 4-OMe 3,5-di-Cl-4-OH 379/381/383 1 A748 H H 4-OMe3,5-di-Br-4-OH 467/469/471 1 A749 H H 4-OMe 3-CO2H 339 1 A750 H H 4-OMe3-OH 311 1 A751 H H 3-OMe 3,5-di-Cl-4-OH 379/381/383 1 A752 H H 3-OMe3,5-di-Br-4-OH 467/469/471 1 A753 H H 3-OMe 3-CO2H-4-Cl 373/375 1 A754 HH 3-OMe 3-CO2H 339 1 A755 H H 3-OMe 3-OH 311 1 A756 H H 3-NO2 4-CH2NH2337 [M − H]− 10 A757 H H 2-OMe 4-CH2NH2 322 [M − H]− 10 A758 H H 3-Me3,4-[S—CH═N] 336 1 A759 H H 3-OMe 3,4-[S—CH═N] 352 1 A760 H H 4-OH3-CO2H-4-Cl 359/361 4 A76l H H 4-NMe2 4-SMe 354 1 A762 H H 4-Cl3-OH-4-OMe 345/347 1 A763 H H 3-NO2 4-(CH2)2CO2H 380[M − H] 1 A764 H H3-NO2 4-(CH2)2CO2Me 396 1 A765 H H 4-Cl 4-(CH2)2CO2Me 385/387 1 A766 H H2-OMe 4-(CH2)2CO2H 367 1 A767 H H 2-OMe 4-(CH2)2CO2Me 381 1 A768 H H4-Cl 3,5-di-Cl-4-Me 381/383/385/387 1 A769 H H 4-Cl 4-trans- 397/399 1CH═CHCO2Et A770 H H 4-CO2Me 3-F-4-Me 355 11 A771 H Me 4-Cl 2-Me 327/3291 A772 H H 3-NO2 4- 522 12 [(CH2)2CONH(CH2)6— NHCOMe] A773 H H 4-Cl 4-511/513 12 [(CH2)2CONH(CH2)6— NHCOMe] A774 H H 2-OMe 4- 507 12[(CH2)2CONH(CH2)6— NHCOMe] A775 H H 3,5-di-Me 3,5-di-Cl-4-OH 377/379/3811 A776 H H 3,5-di-Me 3,5-di-Br-4-OH 465/467/469 1 A777 H H 3,5-di-Me3-CO2H-4-Cl 371/373 1 A778 H H 3,5-di-Me 3-CO2H 337 1 A779 H H 3,5-di-Me3-OMe 323 1 A780 H H 3,5-di-Me 3,4-[OCH2O] 337 1 A781 H H 4-iPr3,5-di-Cl-4-OH 391/393/395 1 A782 H H 4-iPr 3,5-di-Br-4-OH 479/481/483 1A783 H H 4-iPr 3-CO2H-4-Cl 385/387 1 A784 H H 4-iPr 3-CO2H 351 1 A785 HH 4-iPr 3-OMe 337 1 A786 H H 4-iPr 3,4-[OCH2O] 351 1 A787 H H 2-Br3,5-di-Cl-4-OH 427/429/431/433 1 A788 H H 2-Br 3,5-di-Br-4-OH515/517/519/521 1 A789 H H 2-Br 3-CO2H 387/389 1 A790 H H 2-Br 3-OMe373/375 1 A791 H H 2-Br 3,4-[OCH2O] 387/389 1 A792 H H 3,4-di-OMe 3-OMe355 1 A793 H H 3-Cl-4-OMe 3,5-di-Cl-4-OH 413/415/417/419 1 A794 H H3-Cl-4-OMe 3,5-di-Br-4-OH 501/503/505/507 1 A795 H H 3-Cl-4-OMe3-CO2H-4-Cl 407/409/411 1 A796 H H 3-Cl-4-OMe 3-CO2H 371/373 [M − H]− 1A797 H H 3-Cl-4-OMe 3-OMe 359/361 1 A798 H H 4-Me 3,5-di-Cl-4-OH363/365/367 1 A799 H H 4-Me 3,5-di-Br-4-OH 451/453/455 1 ASOO H H 4-Me3-CO2H 323 1 A801 H H 4-Me 3-OMe 309 1 A802 H H 4-Me 3,4-[OCH2O] 323 1A803 H H 2,4-di-Cl 3,5-di-Cl-4-OH 415/417/419/421/423 1 [M − H] A804 H H2,4-di-Cl 3,5-di-Br-4-OH 503/505/507/509/511 1 [M − H] A805 H H2,4-di-Cl 3-CO2H 377/379/381 1 A806 H H 2,4-di-Cl 3-OMe 363/365/367 1A807 H H 2,4-di-Cl 3,4-[OCH2O] 375/377/379[M − H]− 1 A808 H H 3-Cl3,5-di-Cl-4-OH 381/383/385/387[M − H]− 1 A809 H H 3-Cl 3-CO2H 343/345 1A810 H H 3-Cl 3-OMe 329/331 1 A811 H H 3-Cl-4-OMe 3,4-[OCH2O] 373/375 1A812 H H 3-Br 3,5-di-Cl-4-OH 425/427/429/431[M − H]− 1 A813 H H 4-SMe3,5-di-Cl-4-OH 393/395/397 [M − H]− 1 A814 H H 4-F 3,5-di-Cl-4-OH365/367/369 [M − H]− 1 A815 H H 3-Cl 3,4-[OCH2O] 343/345 1 A816 H H 4-Cl3,4-[CO(CH2)4] 381/383 1 A817 H H 4-Cl 3,4-[CH2SO2CH2] 387/389[M − H]− 1A818 H H 4-Cl 3,4-[O-C(Me)═N] 354/356 1 A819 H H 4-Cl 3,4-[OCF2O]379/381 1 A820 H H 4-Cl 3,4-[O(CH2)3O] 371/373 1 A821 H H 2,3-di-F3,5-di-Cl-4-OH 383/385/387[M − H]− 1 A822 H H 2,6-di-Cl 3,5-di-Cl-4-OH415/417/419/421/423 1 [M − H] A823 H H 3,4-di-Cl 3,5-di-Cl-4-OH415/417/419/421/423 1 [M − H]− A824 H H 2-F 3,5-di-Cl-4-OH 367/369/371 1A825 H H 2-Me 3,5-di-Cl-4-OH 363/365/367 1 A826 H H 4-NO2 3,5-di-Cl-4-OH392/394/396 [M − H]− 1 A827 H H 3-OPh 3,5-di-Cl-4-OH 441/443/445 1 A828H H 4-OPh 3,5-di-Cl-4-OH 441/443/445 1 A829 H H 3-NO2-4-C13,5-di-Cl-4-OH 426/428/430/432 [M − H]− 1 A830 H H 4-OH 3-Cl-4-OH331/333 4 A831 H H 4-OH 3-Br-4-OH 375/377 4 A832 H H 4-Cl4-trans-CH═CHCO2H 369/371 13 A833 H H 4-Cl 4-trans- 368/370 14CH═CHCONH2 A834 H Me 4-Cl 4-OMe 343/345 1 A835 H H 3,4,5-tri-F3,5-di-Cl-4-OH 401/403/405 [M − H]− 1 A836 H H 2-NO2 3,5-di-Cl-4-OH392/395/397 [M − H]− 1 A837 H H 3,5-di-F 3,5-di-Cl-4-OH 383/385/387 [M −H]− 1 A838 H H 4-Cl 3-[OC6F5] 481/483 1 A839 H H 4-Cl 2,3-[OCF2O]377/379[M − H]− 1 A840 H H 2-F 3,4-[S—CH═N] 340 1 A841 H H 3-F3,4-[S—CH═N] 340 1 A842 H H 3-Cl 3,4-[S—CH═N] 356/358 1 A843 H H 4-CF33,5-di-Cl-4-OH 415/417/419 [M − H]− 1 A844 H H 3-SCF3 3,5-di-Cl-4-OH447/449/451 [M − H]− 1 A845 H H 4-OCF3 3,5-di-Cl-4-OH 431/433/435 [M −H]− 1 A846 H H 3-CF3 3,5-di-Cl-4-OH 415/417/419 [M − H]− 1 A847 H H3,5-bis-CF3 3,5-di-Cl-4-OH 483/485/487 [M − H] 1 A848 H H 3,4-[OCH2O]3,5-di-Cl-4-OH 393/395/397 1 A849 H H 2-OCH2Ph 3,5-di-Cl-4-OH455/457/459 1 A850 H H 3,4-[(—CH═CH—)2] 3,5-di-Cl-4-OH 399/401/403 1A851 H H 4-Cl 3,4-[N═C(Me)—O] 354/356 1 A852 H H 4-F 3,4-[S—CH═N] 340 1A853 H H 3-Br 3,4-[S—CH═N] 400/402 1 A854 H H 2-Br 3,4-[S—CH═N] 400/4021 A855 Me H 4-Cl 3-CO2H-4-Cl 389/391/393 [M − H]− 1 A856 Me H 4-Cl4-CH2SO2NHMe 420/422 1 A857 Me H 4-Cl 3,5-di-F 349/351 1 A858 Me H 4-Cl3,4-[OCH2O] 357/359 1 A859 Me H 4-Cl 3,5-di-Cl-4-OH 397/399/401/403 1A860 Me H 4-Cl 4-(CH2)2CO2Me 399/401 1 A861 Me H 4-Cl 4-(CH2)2CO2H385/387 1 A862 H H 4-COPh 3,5-di-Cl-4-OH 453/455/457 1 A863 H H 3,4-di-F4-SMe 347 1 A864 H H 3,4-di-F 3,4-[(CH2)3] 341 1 A865 H H 2,4-di-Cl3,4-[S—CH═N] 390/392/394 1 A866 H H 3,4-di-Cl 3,4-[S—CH═N] 390/392/394 1A867 H H 3-F 3,5-di-F 317 [M − H]− 1 A868 H H 3-F 4-CH2SO2NHMe 390 1A869 H H 3-F 4-(CH2)2CO2H 355 1 A870 H H 3-F 3-OMe 313 1 A871 H H 3-F3-Cl 317/319 1 A872 H H 3-F 3-Cl-4-OMe 347/349 1 A873 H H 3-F 3-Cl-4-OH333/335 1 A874 H H 3-F 4-(CH2)3CO2H 367 [M − H]− 1 A875 H H 3-F3,5-di-Me 311 1 A876 H H 3-F 3-Cl-4-Me 331/333 1 A877 H H 3-F H 283 1A878 H H 2-Cl 3-F 315/317 [M − H]− 1 A879 H H 2-Cl 3-OMe 329/331 1 A880H H 2-Cl 3-Cl-4-OMe 363/365/367 1 A881 H H 2-Cl 3-Cl-4-OH 349/351/353 1A882 H H 2-Cl 4-(CH2)3CO2H 385/387 1 A883 H H 2-Cl 3,5-di-OMe 359/361 1A884 H H 2-Cl 3-NO2-4-OH 360/362 1 A885 H H 2-Cl 4-CH2P(O)(OEt)2 449/4511 A886 H H 2-Cl 4-NHCOMe 356/358 1 A887 H H 2-Cl 4-(CH2)2CONH2 370/372 1A888 H H 2-Cl 3-CH2OH 329/331 1 A889 H H 4-Cl 3-Cl-4-OMe 363/365/367 1A890 H H 4-Cl 3-Cl-4-OH 349/351/353 1 A891 H H 4-Cl 3-CN 322/324 [M − H]1 A892 H H 4-Cl 3-CO2Me 357/359 1 A893 H H 4-Cl 2-Me-5-CO2Me 371/373 1A894 H H 4-Cl 3-Cl-4-Me 347/349/351 1 A895 H H 3,4-di-F 3-CO2Me 359 1A896 H H 3,4-di-F 3-CO2H 343 [M − H]− 1 A897 H H 4-Cl 2,3-[S—CH═N]356/358 1 A898 H H 4-Cl 3,4-[N═CH—S] 356/358 1 A899 H H 4-Cl 3,4-380/382[M − H]− 1 [(CH2)2N(COMe)] A900 H H 4-Cl 3,4- 380/382[M − H]− 1[N(COMe)(CH2)27] A901 H H 3,4-di-F 3,4-[S—CH═N] 358 1 A902 H H 4-Cl3,4-[CH═CHCO—O] 367/369 1 A903 H H 2-Cl 4-CH2NHCONHPh 445/447 [M − H]− 1A904 H H 4-Cl 4-OCH2CO2Me 385/387 [M − H]− 1 A905 H H 2-Cl 4-(CH2)2CO2H371/373 1 A906 H H 2,6-di-Cl 3,4-[S—CH═N] 390/392/394 1 A907 H H 3-Cl3-CO2H-4-Cl 377/379/381 1 A908 H H 3-Cl 3-Cl-4-OH 349/351/353 1 A909 H H3-Cl 3,5-di-F 335/337 1 A910 H H 3-Cl 3-CH2OH 329/331 1 A9ll H H 3-Cl3-OH 315/317 1 A912 H H 3-Cl 4-CH2SO2NHMe 406/408 1 A9l3 H H 2,4-di-OMe3,5-di-Cl-4-OH 407/409/411 [M − H]− 13 A914 H H 2-OEt 3,5-di-Cl-4-OH391/393/395 [M − H]− 13 A915 H H 4-OnBu 3,5-di-Cl-4-OH 419/421/423 [M −H]− 13 A916 H H 3,4,5-tri-OMe 3,5-di-Cl-4-OH 439/441/443 13 A917 H H2-OPh 3,5-di-Cl-4-OH 441/443/445 13 A918 H H 4-Ph 3,5-di-Cl-4-OH425/427/429 13 A9l9 H H 2-OMe-5-Br 3,5-di-Cl-4-OH 457/459/461 13 A920 HH 4-Cl 4-CH2NHCONHPh 445/447 [M − H]− 1 A921 H H 4-Cl 3-CO2Me-4-Cl391/393/395 1 A922 H H 2,3-di-F 3-CO2H-4-Cl 379/381 1 A923 H H3,4,5-tri-F 3-CO2H-4-Cl 395/397 [M − H]− 1 A924 H H 3,5-di-F 3-CO2H-4-Cl377/379 [M − H]− 1 A925 H H 2-NO2 3-CO2H-4-Cl 388/390 1 A926 H H3,4-di-F 3-CO2H-4-Cl 377/379 [M − H]− 1 A927 H H 2,3-di-F 3,4-[OCH2O]345 1 A928 H H 3,4,5-tri-F 3,4-[OCH2O] 363 1 A929 H H 2,3-di-F 3,5-di-F337 22 A930 H H 2-F 3-CH2OH 313 1 A931 H H 2,3-di-F 3-CH2OH 331 1 A932 HH 3,4,5-tri-F 3-CH2OH 349 1 A933 H H 3,5-di-F 3-CH2OH 331 1 A934 H H2-NO2 3-CH2OH 338 [M − H]− 1 A935 H H 3,4-di-F 3-CH2OH 331 1 A936 H H2-OPh 3-CH2OH 387 1 A937 H H 2,4-di-Cl 3-CH2OH 363/365/367 1 A938 H H2,3-di-F 3-OH 317 1 A939 H H 3,5-di-F 3-OH 317 1 A940 H H2,3-[(—CH═CH—)2] 3,5-di-Cl-4-OH 399/401/403 13 A941 H H 4-Cl 4-SCH2CO2H389/391 13 A942 H H 4-Cl 3,4-[O(CH2)2O] 357/359 1 A943 H H 3,4-di-Cl3-CO2H-4-Cl 409/411/413/415 1 [M − H]− A944 H H 3,4-di-Cl 3-Cl-4-OH383/385/387/389 1 A945 H H 3,4-di-Cl 3,5-di-F 367/369/371 [M − H] 1 A946H H 3,4-di-Cl 3-CH2OH 363/365/367 1 A947 H H 3,4-di-Cl 3-OH 349/351/3531 A948 H H 3,4-di-Cl 4-CH2SO2NHMe 438/440/442 [M − H]− 1 A949 H H4-SO2Me 3-CO2H-4-Cl 419/421 [M − H]− 1 A950 H H 4-SO2Me 3,4-[OCH2O] 386[M]− 1 A951 H H 4-SO2Me 3-Cl-4-OH 391/393 [M − H]− 1 A952 H H 4-SO2Me3,5-di-F 379 1 A953 H H 2-OMe-5-Br 3-CO2H-4-Cl 451/453/455 1 A954 H H2-OMe-5-Br 3,4-[OCH2O] 417/419 1 A955 H H 2-OMe-5-Br 3-Cl-4-OH423/425/427 1 A956 H H 2-OMe-5-Br 3,5-di-F 409/411 1 A957 H H 2-OMe-5-Br3-CH2OH 403/405 1 A958 H H 2-OMe-5-Br 3-OH 389/391 1 A959 H H 2-Me3,4-[OCH2O] 323 1 A960 H H 2-Me 3-Cl-4-OH 329/331 1 A961 H H 2-Me3-CH2OH 309 1 A962 H H 2-Me 3-OH 295 1 A963 H H 3-Br 3-CO2H-4-Cl419/421/423 [M − H]− 1 A964 H H 3-Br 3,4-[OCH2O] 387/389 1 A965 H H 3-Br3-Cl-4-OH 393/395/397 1 A966 H H 3-Br 3,5-di-F 379/381 1 A967 H H 4-Cl4-trans—CH═CHPh 401/403 1 A968 H H 4-Cl 4-SCH2CO— 446/448 17 NH(CH2)2OMeA969 H H 2-F 3-CO2H-4-Cl 361/363 1 A970 H H 2,4-di-Cl 3-CO2H-4-Cl411/413/415/417 1 A971 H H 2-F 3,4-[OCH2O] 327 1 A972 H H 3,5-di-F3,4-[OCH2O] 345 1 A973 H H 2-NO2 3,4-[OCH2O] 354 1 A974 H H 3,4-di-F3,4-[OCH2O] 345 1 A975 H H 2-OPh 3,4-[OCH2O] 401 1 A976 H H 3,4-di-Cl3,4-[OCH2O] 377/379/381 1 A977 H H 2-F 3-Cl-4-OH 333/335 1 A978 H H2,3-di-F 3-Cl-4-OH 351/353 1 A979 H H 3,4,5-tri-F 3-Cl-4-OH 369/371 1A980 H H 3,5-di-F 3-Cl-4-OH 351/353 1 A981 H H 2-NO2 3-Cl-4-OH 360/362 1A982 H H 3,4-di-F 3-Cl-4-OH 351/353 1 A983 H H 2-OPh 3-Cl-4-OH 407/409 1A984 H H 2,4-di-Cl 3-Cl-4-OH 383/385/387/389 1 A985 H H 2-F 3,5-di-F 3191 A986 H H 3,4,5-tri-F 3,5-di-F 353 [M − H]− 1 A987 H H 3,5-di-F3,5-di-F 335 [M − H]− 1 A988 H H 3,4-di-F 3,5-di-F 335 [M − H]− 1 1 A989H H 2-F 3-OH 299 1 A990 H H 3,4,5-tri-F 3-OH 335 1 A991 H H 2-NO2 3-OH326 1 A992 H H 3,4-di-F 3-OH 317 1 A993 H H 2-OPh 3-OH 373 1 A994 H H2,4-di-Cl 3-OH 349/351/352 1 A995 H H 4-Br 4-SO2NH2 420/422 [M − H]− 3A996 H H 4-Cl 3-SO2NHnBu 434/436 1 A997 H H 4-Cl 2,3-[N═CH—CH═CH]350/352 13 A998 H H 2-OEt 3-Cl 343/345 1 A999 H H 2-OPh 3-Cl 391/393 1A1000 H H 2-OMe-5-Br 3-Cl 405/407/409 [M − H]− 1 A1001 H H 3-F3-SO2NHnBu 418 1 A1002 H H 4-Cl 2-Me-5-CO2H 355/357 [M − H]− 13 A1003 HH 2-Cl 3-CH2CO2H 357/359 13 A1004 H H 4-Cl 2-OH-5-CO2H 359/361 13 A1005H H 2-F-6-Cl H 317/319 1 A1006 H H 2-F-6-Cl 3-Br 395/397/399 1 A1007 H H2-F-6-Cl 4-SMe 363/365 1 A1008 H H 2-F-6-Cl 4-Me 331/333 1 A1009 H H2-F-6-Cl 3,4-[OCH2O] 361/363 1 A1010 H H 2-F-6-Cl 3,4-[(CH2)3] 357/359 1A1011 H H 2-F-6-Cl 4-CH2SO2NHMe 424/426 1 A1012 H H 4-I H 391 1 A1013 HH 3-F 2-Me 297 1 A1014 H H 3-F 3-Me 297 1 A1015 H H 3-F 3-CH2OH 313 1A1016 H H 3-F 3-F 301 1 A1017 H H 3-F 3,5-di-OMe 343 1 A1018 H H 3-F3,S-di-Br-4-Me 453/455/457 1 A1019 H H 3-F 4-CH2P(O)(OEt)2 433 1 A1020 HH 3-F 4-F 301 1 A1021 H H 3-F 4-OMe 313 1 A1022 H H 3-F 4-CH2NHCOPh 41613 A1023 H H 3-F 4-CH2NHCOMe 354 13 A1024 H H 4-Cl 4-CH2NHCOMe 368/370[M − H]− 13 A1025 H H 2,6-di-F 3,5-di-Cl-4-OH 385/387/389 13 A1026 H H4-I 4-CH2SO2NHMe 498 1 A1027 H H 2,5-di-Me 3,5-di-Cl-4-OH 375/377/379 [M− H]− 13 A1028 H H 2-F-6-Cl 3,5-di-Cl-4-OH 399/401/403/405 [M − H]− 13A1029 H H 2-OCF3 3,5-di-Cl-4-OH 431/433/435 [M − H]− 13 A1030 H H 3-F3-CN 306 [M − H]− 1 A1031 H H 3-F 3,4-di-Cl 351/353/355 1 A1032 H H 4-I4-Me 403 [M − H]− 1 A1033 H H 4-I 3-[trans- 522/524 1 CH═CHCONMe2]-4- ClA1034 H H 3-F 3-[trans- 412/414 [M − H]− 1 CH═CHCONMe2]-4- Cl A1035 H H3-F 2-F 301 1 A1036 H H 3-F 2-Me-S-Cl 331/333 1 A1037 H H 3-F 2-Me-4-OMe327 1 A1038 H H 3-F 3-COPh 387 1 A1039 H H 3-F 3-COMe 325 1 A1040 H H3-F 4-(CH2)2CONH2 354 1 A1041 H H 2,6-di-F 3-Cl 335/337 1 A1042 H H2-F-6-Cl 3-Cl 351/353/355 1 A1043 H H 2,5-di-F 3-Cl 335/337 1 A1044 H H2,5-di-Me 3-Cl 327/329 1 A1045 H H 2-I 3-Cl 425/427 1 A1046 H H 2-OCF33-Cl 383/385 1 A1047 H H 2-F-6-Cl 4-(CH2)2CONH2 388/390 1 A1048 H H 4-I3,5-di-Cl 457/459/461 [M − H]− 1 A1049 H H 4-I 4-(CH2)2CONH2 462 1 A1050H H 3-F 4-OPh 375 1 A1051 H H 4-I 3,5-di-Cl-4-OH 347/349/351 [M − I]− 13A1052 H H 3-F 4-(CH2)2NHCOPh 430 13 A1053 H H 3-F 3-[4-Methylpiperazin-411 20 1-yl]-4-OMe A1054 H H 3-F 3,5-di-Cl-4-Me 363/365/367 [M − H]− 1A1055 H H 2,3-di-F 3,5-di-Cl-4-Me 383/385/387 1 A1056 H H 4-Br3,5-di-Ci-4-Me 425/427/429/431 1 A1057 H H 2,5-di-F 3-Br 379/381 1 A1058H H 2-OCF3 3-Br 427/429 1 A1059 H H 2,5-di-Me 4-Me 307 1 A1060 H H 2-I4-Me 405 1 A1061 H H 2-OCF3 4-Me 363 1 A1062 H H 4-I 3,5-di-Cl-4-Me473/475/477 1 A1063 H H 2-Cl 3,5-di-Cl-4-Me 381/383/3851387 1 A1064 H H3-Me 3,5-di-Cl-4-Me 361/363/365 1 A1065 H H 2,4-di-Cl 3,5-di-Cl-4-Me415/417/419/421/423 1 1 A1066 H H 2-I 3-Br 469/471 1 A1067 H H 2,6-di-F3-Br 379/381 1 A1068 H H 2,5-di-F 4-SMe 347 1 A1069 H H 2,5-di-Me 4-SMe339 1 A1070 H H 2-I 4-SMe 437 1 A1071 H H 2-OCF3 4-SMe 395 1 A1072 H H2,6-di-F 4-SMe 347 1 A1073 H H 2,5-di-F 4-Me 315 1 A1074 H H 2,6-di-F4-Me 315 1 A1075 H H 2,5-di-F 3,4-[OCH2O] 345 1 A1076 H H 2,5-di-Me3,4-[OCH2O] 337 1 A1077 H H 2-I 3,4-[OCH2O] 435 1 A1078 H H 2-OCF33,4-[OCH2O] 393 1 A1079 H H 2,5-di-F 3,4-[(CH2)3] 341 1 A1080 H H2,5-di-Me 3,4-[(CH2)3] 333 1 A1081 H H 2-I 3,4-[(CH2)3] 431 1 A1082 H H2-OCF3 3,4-[(CH2)3] 389 1 A1083 H H 2,6-di-F 3,4-[(CH2)3] 341 1 A1084 HH 2-OCF3 4-(CH2)2CONH2 420 1 A1085 H H 2,5-di-F H 301 1 A1086 H H2,5-di-Me H 293 1 A1087 H H 2-I H 391 1 A1088 H H 2-OCF3 H 349 1 A1089 HH 2,6-di-F H 301 1 A1090 H H 2,3-di-F 3-CH2CONH2 358 1 A1091 H H2,3-di-F 3-CH2CONHMe 372 1 A1092 H H 2,3-di-F 3-CONHMe 358 1 A1093 H H2,3-di-F 3-CONH2-4-Me 358 1 A1094 H H 2,3-di-F 3-CONH(CH2)2OMe 402 1A1095 H H 3-F 3-CH2CONH2 340 1 A1096 H H 3-F 3-CH2CONHMe 354 1 A1097 H H3-F 3-CONHMe 340 1 A1098 H H 3-F 3-CONH2-4-Me 340 1 A1099 H H 3-F3-CONH(CH2)2OMe 384 1 A1100 H H 3-F 3-CF3 351 1 A1101 H H 3-F 4-nBu 3391 A1102 H H 3-F 4-OnBu 355 1 A1103 H H 3-F 2-Et 311 1 A1104 H H 3-F2-iPr 325 1 AIIOS H H 3-F 3,4-[OCF2O] 363 1 A1106 H H 3-F 3,4- 366 1[(CH2)2N(COMe] A1107 H H 3-F 3,4-[O(CH2)3O] 355 1 A1108 H H 3-F3,4-di-Me 311 1 A1109 H H 3-F 3,4-di-OMe 343 1 A1110 H H 3-F 3-Br-4-OCF3445/447 1 A1111 H H 3-F 3-CO2Me 341 1 A1112 H H 3-F 3-CONH2 326 1 A1113H H 3-F 3-F-A-Me 315 1 A1114 H H 3-F 3-I 409 1 A1115 H H 3-F 3-OCH2Ph389 1 A1116 H H 3-F 4-CH2NHBOC 410[M − H]− 1 A1117 H H 3-F 4-Cl 317/3191 A1118 H H 3-F 4-NHCOMe 340 1 A1119 H H 3-F 4-OCH2Ph 389 1 A1120 H H3-F 4-tBu 339 1 A1121 H H 3-F 2,3-[OCF2O] 363 1 A1122 H H 3-F 2-Me-3-Br375/377 1 A1123 H H 3-F 2-Me-3-Cl 331/333 1 A1124 H H 3-F 2-Me-5—CH2OH325 [M − H]− 1 A1125 H H 3-F 2-OPh 375 1 A1126 H H 3-F 3,4-[CH2SO2CH2]373 1 A1127 H H 3-F 3-Br-4-Cl 395/397/399 1 A1128 H H 3-F 3-OiPr 341 1A1129 H H 3-F 3-SO2CF3 413 [M − H]− 1 A1130 H H 3-F 2,3-di-Me 311 1A1131 H H 3-F 2,4-di-Me 311 1 A1132 H H 3-F 2-Me-4-Cl 331/333 1 A1133 HH 3-F 2-OMe 313 1 A1134 H H 3-F 2-Ph 359 1 A1135 H H 3-F 2-SMe 329 1A1136 H H 3-F 3-Et 311 1 A1137 H H 2,5-di-Me 4-(CH2)2CONH2 364 1 A1138 HH 2,5-di-F 4-(CH2)2CONH2 372 1 A1139 H H 2-I 4-(CH2)2CONH2 462 1 A1140 HH 2,6-di-F 4-(CH2)2CONH2 372 1 A1141 H H 2,6-di-F 3,4-[OCH2O] 345 1A1142 H H 3,5-di-F 3,5-di-Cl-4-Me 383/385/387 1 A1143 H H 2,5-di-F4-CH2SO2NHMe 408 1 A1144 H H 2,5-di-Me 4-CH2SO2NHMe 400 1 A1145 H H 2-I4-CH2SO2NHMe 498 1 A1146 H H 2-OCF3 4-CH2SO2NHMe 456 1 A1147 H H2,6-di-F 4-CH2SO2NHMe 408 1 A1148 H H 4-Cl 4-CH2NHCOPh 432/434 13 A1149H H 2,3-di-F 3,4-[S—CH═N] 358 1 A1150 H H 4-Cl 4-trans-CH═CH-(4- 417/4191 OH-Ph) A1151 H H 4-I 4-Cl 425/427 1 A1152 H H 4-I 4-OMe 421 1 A1153 HH 3-F 4-trans- 352 13 CH═CHCONH2 A1154 H H 2,3-di-F 4-trans- 370 13CH═CHCONH2 A1155 H H 3-F 3-[4-(COCHCl2)- 507/509/511 13Piperazin-1-yl]-4-OMe A1156 H H 3-F 4-trans-CH═CH-(4- 401 1 OH-Ph) A1157H H 3-F 4-[1,2,3-Thiadiazol-4- 367 1 yl] A1158 H H 3-F3-[O-(Pyrimidin-2-yl)] 377 13 A1159 H H 3-F 4-[N(Me)(Pyrimidin- 390 202-yl)] A1160 H H 3-F 3,4-[S—C(Me)═N] 354 1 A1161 H H 3-F3,4-[O—C(NHMe)═N] 353 1 A1162 H H 2,3-di-F 4-[Morpholin-1-yl] 386 1A1163 H H 2,3-di-F 3,4-[OC(NHMe)═N] 371 13 A1164 H H 3-F 3,4-[OC(═O)NH]340 13 A1165 H H 3-F 3-(CH2OH)-4-OMe 341 [M − H]− 13 A1166 H H 3-F3-(CH2NMe2)-4-OMe 370 13 A1167 H H 2,3-di-F 3-Cl 335/337 1 A1168 H(CH2)2O 2,3-di-F H 345 1 H A1169 H H 2,3-di-F 4-CH2SO2NHMe 408 1 A1170 HH 2,3-di-F 3-CH2CO2H 359 13 A1171 H H 2,3-di-F 4-CH2CO2H 359 13 A1172 HH 2,3-di-F 4-OCH2CO2H 375 13 A1173 H H 2,3-di-F 4-(CH2)2CO2H 373 13A1174 H H 2,3-di-F 4-(CH2)3CO2H 385 [M − H]− 13 A1175 H H 2,3-di-F4-NMe2 344 1 A1176 H H 2,3-di-F 2,4-di-F 337 1 A1177 H H 2,3-di-F3,4-di-F 337 1 A1178 H H 2,3-di-F 2,3-di-F 337 1 A1179 H H 2,3-di-F2,5-di-F 337 1 A1180 H H 2,3-di-F 4-SPh 409 1 A1181 H H 2,3-di-F 4-OPh393 1 A1182 H H 2,3-di-F 4-NHPh 392 1 A1183 H H 2,3-di-F 2-OMe-3-F 349 1A1184 H H 2,3-di-F 3-Cl-4-Me 349/351 1 A1185 H H 2,3-di-F 4-NHSO2Me 3941 A1186 H H 2,3-di-F 3-[CH2-(1,3- 430 1 Thiazolidine-2,4-dion- 5-yl]A1187 H H 3-F 4-[OCH2-(1-Methyl- 410 1 piperazin-4-yl)] A1188 H (CH2)2O2-Cl H 343/345 3 H A1189 H (CH2)2O 3,5-di-Me H 337 3 H A1190 H H2,3-di-F 3,4-[N═N—NH] 342 1 A1191 H H 2,3-di-F 3,4-[CH═N—NH] 341 1 A1192H H 2,3-di-F 3,4-[NH-N═CH] 341 1 A1193 H H 2,3-di-F 3,4-[OCF2O] 379 [M −H] 1 A1194 H H 2,3-di-F 3,5-di-Cl 367/369/371 [M − H]− 1 A1195 H H2,3-di-F 3,5-di-Me 327 [M − H]- 1 A1196 H H 2,3-di-F 2-F 317 [M − H]− 1A1197 H H 2,3-di-F 3-Cl-4-OMe 363/365 [M − H]− 1 A1198 H H 2,3-di-F3-CO2H 343 [M − H]− 1 A1199 H H 2,3-di-F 3-F 319 1 A1200 H H 2,3-di-F3-F-4-Me 333 1 A1201 H H 2,3-di-F 3-I 425 [M − H]− 1 A1202 H H 2,3-di-F3-OMe 329 [M − H]− 1 A1203 H H 2,3-di-F 4-CH2CH2CONH2 370 [M − H]− 1A1204 H H 2,3-di-F 4-F 317 [M − H]− 1 A1205 H H 2,3-di-F 4-Cl 333/335 [M− H]− 1 A1206 H H 2,3-di-F 4-NHCOMe 358 1 A1207 H H 2,3-di-F 4-OMe 331 1A1208 H H 2,3-di-F 4-CH2CONH2 358 1 A1209 H H 2,3-di-F 3-CH2OMe 343 [M −H]− 1 A1210 H H 2,3-di-F 3-CH(OH)Ph 405 [M − H]− 1 A1211 H H 3,5-di-Cl4-CH2SO2NHMe 438/440/442 [M − H] 1 A1212 H H 3,5-di-Cl 4-CH2CH2CONH2402/404/406 [M − H] 1 A1213 H H 3,5-di-Cl 3,5-di-F 367/369/371 [M − H] 1A1214 H H 3,5-di-Cl 4-Me 345/347/349 [M − H]− 1 A1215 H H 3,5-di-Cl 3-Cl365/367/369/371 [M − H]− 1 A1216 H H 3,5-di-Cl H 331/333/335[M − H]− 1A1217 H H 2,3,5-tri-F 4-CH2SO2NHMe 424 [M − H]− 1 A12I8 H H 2,3,5-tri-F4-CH2CH2CONH2 390 1 A1219 H H 2,3,5-tri-F 3,5-di-F 353 [M − H]− 1 AI220H H 2,3,5-tri-F 4-Me 333 1 A1221 H H 2,3,5-tri-F 3-Cl 351/353 [M − H] 1A1222 H H 2,3,5-tri-F 3,4-[(CH2)3] 359 1 A1223 H H 2,3,5-tri-F H 319 1A1224 H H 2,3-di-F 3,4-[O(CH2)3O] 373 1 A1225 H H 2,3-di-F 3-F-4-OMe 3491 A1226 H H 2,3-di-F 4-(CH2)2OH 345 1 A1227 H H 2,3-di-F 4-CH2CN 340 1A1228 H H 3,5-di-Cl 3,4-[(CH2)3] 371/373/375 [M − H]− 1 A1229 H H2,3-di-F 3-[CO2H]-4- 401 1 [CH2CO2H] A1230 H H 2,3-di-F4-[4-Methyl-piperazin- 399 20 1-yl] A1231 H H 2,3-di-F 3,4-[O(CH2)2O]357 [M − H]− 1 A1232 H H 2,3-di-F 4-[CH2CO- 426 [M − H]− 1(Morpholin-1-yl)] A1233 H H 2,3-di-F 4- 416 1 [CH2CONH(CH2)2O Me] A1234H H 3-NO2 4- 578 [M − H]− 12 [(CH2)2CONH(CH2)6 NHBOC] A1235 H H 3-NO2 4-480 10 [(CH2)2CONH(CH2)6 NH2] A1236 H H 3-NO2 4- 706 9 [(CH2)2CONH(CH2)6NH-Biotinyl] A1237 H H 2,3-di-F 3- 385 [M − H]− 13 [CH2CH(Me)CO2H] A1238H H 2,3,5-tri-F 3,5-di-Cl-4-OH 401/403/405 [M − H]− 13 A1239 H H3,5-di-Cl 3,5-di-Cl-4-OH 415/417/419/421/423 13 [M − H] A1240 H H3,5-di-F 2,3-di-F 337 1 A1241 H H 2,3-di-F 4-[SCH2CO2H]391 13

[0638] TABLE B Encompassing compounds of general formula (I) andsubstituents R, R¹, R² and R³ are listed in Table B. (I)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example No. R R¹ R² R³[M − H]⁻ are Indicated) See Example No. B1 Me Me Indol-3-yl Ph 332 3 B2H H Indol-3-yl H 228 5 B3 H Me Indol-3-yl Ph 318 5 B4 H H Ph H 189 1 B5H H Ph CH2Ph 279 1 B6 CH2Ph H Ph CH2Ph 369 1 B7 H Et 4-CF3—Ph Et 313 1B8 H Me 4-OMe—Ph CH2Ph 323 1 B9 H Et 4-Cl—Ph Et 279/281 1 B10 H Me4-Cl—Ph CH2Ph 327/329 1 B11 H Me 4-Cl—Ph (CH2)2Ph 341/343 1 B12 H Et PhEt 245 1 B13 H Me Ph CH2Ph 293 1 B14 H Me Ph (CH2)2Ph 307 1 B15 H(CH2)2OMe 4-Cl—Ph (CH2)2OMe 339/341 1 B16 H H 3-NO2—Ph 4-Me-Oxazol-2-yl315 1 B17 H Me 3-NO2—Ph CH2Ph 338 1 B18 H Me 3-NO2—Ph (CH2)2Ph 352 1 B19H H 3-NO2—Ph Cyclohexyl 314[M − H]− 1 B20 H H 2-OMe—Ph Fluoren-2-yl 3831 B21 H H 3-NO2—Ph Fluoren-2-yl 396[M − H]− 1 B22 H H 4-Cl—PhDibenzofuran-2-yl 389/391 1 B23 H H 4-Cl—Ph Dibenzofuran-3-yl 389/391 1B24 H H 4-Cl—Ph (2-Acetylbenzofuran-5-yl) 381/383 1 B25 H H 3-NO2—Ph H234 16 B26 H H 4-Cl—Ph 2,6-di-Me-pyridin-3-yl 328/330 13 B27 H H 4-Cl—Ph(CH2)2OMe 281/283 18 B28 H H 4-I—Ph (CH2)2OMe 373 18 B29 H H 4-Cl—Ph2-Methylpyridin-3-yl 314/316 13 B30 H H 4-Cl—Ph 2-Chloropyridin-5-yl332/334/336[M − H]− 13 B31 H H 4-Cl—Ph Quinolin-3-yl 350/352 13 B32 H H4-Cl—Ph Pyrimidin-2-yl 301/303 13 B33 Me H 3-F—Ph H 219[M − H]− 16 B34 HH 2,3-di-F—Ph 2,6-di-Me-pyridin-3-yl 330 13

[0639] TABLE C Encompassing compounds of general formula (XXX-2),wherein group R² of formula (I) is a phenyl ring, optionally substitutedby one or more substituents R¹⁰ and the moiety —NR¹R³ of formula (I)represents a heterocyclyl moiety of general formula (XXX-3) andsubstituents R, R¹⁰ and P-Q are listed in Table C. (XXX-2)

(XXX-3)

[M + H]⁺ Observed; For (Unless [M]⁻ or Procedure See Example No. R R¹⁰P-Q [M − H]⁻ are Indicated) Example No. C1 H 4-OMe (CH2)2O(CH2)2 289 1C2 H 4-Cl (CH2)4 277/279 1 C3 H 4-Cl (CH2)2O(CH2)2 293/295 1 C4 H 4-Cl(CH2)3CH(Me)CH2 305/307 1 C5 H 4-Cl (CH2)3CH(CONH2)CH2 332/334[M − H]− 1C6 H H (CH2)3CH(CONH2)CH2 300 1 C7 H 4-OMe (CH2)3CH(CONH2)CH2 330 1 C8 HH (CH2)4 243 1 C9 H 4-Cl (CH2)3CH(CH2OH)CH2 321/323 1 C10 H 4-Cl (CH2)5291/293 1 C11 H 4-Cl (CH2)2CH(CH2Ph)(CH2)2 381/383 1 C12 H 4-Cl(CH2)2CH(OH)(CH2)2 307/309 1 C13 H 3-NO2 (CH2)3CH(Me)CH2 316 1 C14 H2,4-di-Cl (CH2)5 325/327/329 1 C15 H 2,4-di-Cl (CH2)2O(CH2)2 327/329/3311 C16 H 2,4-di-Cl (CH2)2S(CH2)2 341/343/345[M − H]− 1

[0640] TABLE D Encompassing compounds of general formula (XXX-4),wherein group R² of formula (I) is a phenyl ring, optionally substitutedby one or more substituents R¹⁰ and the moiety —NR¹R³ of formula (I)represents a heterocyclyl moiety of general formula (XXX-5), optionallysubstituted by substituents R^(12a), R^(12b) and R^(12c) andsubstituents R, R¹⁰, R^(12a), R^(12b), R^(12c), X—Y and Z are listed inTable D. (XXX-4)

(XXX-5)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example No. R R¹⁰R^(12a) R^(12b) R^(12c) X—Y Z [M − H]⁻ are Indicated) See Example No. D1H 4-CF3 H H H CH═N bond 358 2 D2 H 4-Cl H H H (CH2)2 bond 325/327 1 D3 H4-Cl H H H (CH2)2 CH2 393/341 1 D4 H 4-Cl H H H (CH2)3 bond 339/341 1 D5H 4-Cl NO2 H H (CH2)2 bond 370/372 1 D6 H 3-NO2 H H H (CH2)2 CH2 350 1D7 H 4-OMe H H H (CH2)2 bond 321 1 D8 H 4-Cl H H H (CH2)2 (CH2)2 353/3551 D9 H 3-NO2 H H H (CH2)2 (CH2)2 364 1 D10 H 3-CF3 H H H (CH2)2 bond 3591 D11 H 3,5-di-F H H H (CH2)2 bond 327 1 D12 H 3-NO2 H H H (CH2)2 bond336 1 D13 H 2-OMe H H H (CH2)2 bond 321 1 D14 H 2-Cl H H H (CH2)2 bond325/327 1 D15 H 2-OMe H H H (CH2)2 CH2 335 1 D16 H 2-OMe H H H CH(Me)CH2bond 335 1 D17 H 2-Cl H H H CH(Me)CH2 bond 339/341 1 D18 H 3,5-di-F H HH CH(Me)CH2 bond 341 1 D19 H 3-NO2 H H H CH═CH bond 334 15 D20 H 3-NO2 HH H CH(CO2H)CH2 bond 380 1 D21 H 3,4-di-F H H H (CH2)2 bond 327 1 D22 H3-NO2 H H H CH(CO2Me)CH2 bond 392[M − H]− 1 D23 H 4-I H H H (CH2)2 bond417 1 D24 H 3-Cl H H H (CH2)2 bond 325/327 1 D25 H 4-Br H H H (CH2)2bond 369/371 1 D26 H 3-Br H H H (CH2)2 bond 369/371 1 D27 H 2-Me H H H(CH2)2 bond 305 1 D28 H 3-F H H H (CH2)2 bond 309 1 D29 H 2,4-di-Cl H HH (CH2)2 bond 359/361/363 1 D30 H 2-Br H H H (CH2)2 bond 369/371 1 D31 H2-F H H H (CH2)2 bond 309 1 D32 H 4-COPh H H H (CH2)2 bond 394[M]− 1 D33H 2-NO2 H H H (CH2)2 bond 336 1 D34 H 3,4,5-tri-F H H H (CH2)2 bond343[M − H]− 1 D35 H 2-OEt H H H (CH2)2 bond 335 1 D36 H 3-F[4-Ethyl-pipera- OMe H (CH2)2 bond 451 20 zin-1-yl] D37 H 3-F H H HCH(Me)CH2 bond 323 1 D38 H 2,3-di-F H H H CH(Me)CH2 bond 341 D39 H 2-F HH H CH(Me)CH2 bond 323 1 D40 H 2-Me H H H CH(Me)CH2 bond 319 1 D41 H2-Br H H H CH(Me)CH2 bond 383/385 1 D42 H 4-OMe H H H CH(Me)CH2 bond 3351 D43 H 4-Cl H H H CH(Me)CH2 bond 339/341 1 D44 H 4-I H H H CH(Me)CH2bond 431 1 D45 H 3-Me H H H CH(Me)CH2 bond 319 1 D46 H 3,5-di-Me H H HCH(Me)CH2 bond 333 1 D47 H 3-F H H H (CH2)3 bond 323 1 D48 H 3-F[4-(BOC)-Pipera- OMe H (CH2)2 bond 521[M − H]− 20 zin-1-yl] D49 H 3-F[4-Me-Pipera- Cl H (CH2)2 bond 441/443 20 zin-1-yl] D50 H 3-F[4-Me-Pipera- Me H (CH2)2 bond 421 20 zin-1-yl] D51 H 2-Cl H H HCH(CH2OH)CH2 bond 355/357 1 D52 H 2-OMe H H H CH(CH2OH)CH2 bond 351 1D53 H 3-F H H H CH(CH2OH)CH2 bond 339 1 D54 H 2,3-di-F H H HCH(CH2OH)CH2 bond 357 1 D55 H 3,5-di-F H H H CH(CH2OH)CH2 bond 357 1 D56H 3,5-di-Me H H H CH(CH2OH)CH2 bond 349 1 D57 H 2-Cl H H H CH2CH(Me)bond 339/341 1 D58 H 3-F H H H CH2CH(Me) bond 323 1 D59 H 3-F [Pipera-OMe H (CH2)2 bond 421[M − H]− 20 zin-1-yl] D60 H 2-Cl H H H CH2CH(CH2OH)bond 355/357 20 D61 H 3-F H H H CH2CH(CH2OH) bond 339 20 D62 H 2,3-di-FH H H CH2CH(CH2OH) bond 357 20 D63 H 2,3-di-F H H H CH2 CH2 325[M − H]−20 D64 H 2,3-di-F H H H CH2C(Me2) bond 355 1 D65 H 2,3-di-F OMe H H(CH2)2 bond 357 1 D66 H 2,3-di-F H Br H (CH2)2 bond 405/407 1 D67 H 2-ClH H H CH2C(Me2) bond 353/355 1 D68 H 2-Cl H F H (CH2)2 bond 343/345 1D69 H 2,3-di-F NO2 H H (CH2)2 bond 372 1 D70 H 3,5-di-Me OMe H H (CH2)2bond 349 1 D71 H 2,3-di-F H H H CH2CH(Me) bond 341 1 D72 H 2,3-di-F OMeOMe H (CH2)2 bond 387 1 D73 H 2,3-di-F H H Br (CH2)2 bond 405/407 1 D74H 2,3-di-F H F H (CH2)2 bond 345 1 D75 H 2,3-di-F F H H (CH2)2 bond 3451 D76 H 2,3-di-F CF3 Me H (CH2)2 bond 409 1 D77 H 2,3-di-F CF3 OMe H(CH2)2 bond 425 1 D78 H 2-Cl OMe H H (CH2)2 bond 355/357 1 D79 H 2-Cl HH Br (CH2)2 bond 403/405/407 1 D80 H 2-Cl H Br H (CH2)2 bond 403/405/4071 D81 H 2-Cl F H H (CH2)2 bond 343/345 1 D82 H 2-Cl NO2 H H (CH2)2 bond370/372 1 D83 H 2-Cl CF3 Me H (CH2)2 bond 407/409 1 D84 H 2-Cl CF3 OMe H(CH2)2 bond 423/425 1 D85 H 3,5-di-Me H H H CH2CH(Me) bond 333 1 D86 H3,5-di-Me H H H CH2C(Me)2 bond 347 1 D87 H 3,5-di-Me OMe OMe H (CH2)2bond 379 1 D88 H 3,5-di-Me H H Br (CH2)2 bond 397/399 1 D89 H 3,5-di-MeH Br H (CH2)2 bond 397/399 1 D90 H 3,5-di-Me F H H (CH2)2 bond 337 1 D91H 2,3-di-F H NHSO2Me H (CH2)2 bond 420 1 D92 H 2-Cl H NHSO2Me H (CH2)2bond 418/420 1 D93 H 2,3-di-F H H H (CH2)2 bond 327 1 D94 H 3,5-di-Me HH H (CH2)2 bond 319 1 D95 H 2-Cl OMe OMe H (CH2)2 bond 385/387 1 D96 H3,5-di-Me NO2 H H (CH2)2 bond 364 1 D97 H 2-Cl H H H CH(CONH2)CH2 bond368/370 3 D98 H 2,3-di-F H H H CH(CONH2)CH2 bond 370 3 D99 H 3,5-di-Me HH H CH(CONH2)CH2 bond 362 3 D100 H 3,5-di-Cl H H H (CH2)2 bond359/361/363 1 D101 H 2,3,5-tri-F H H H (CH2)2 bond 343[M − H]− 1 D102 H3-NO2 H H H CH(CH2OH)CH2 bond 366 13 D103 H 4-I H H H CH(CH2OH)CH2 bond447 13 D104 H 4-I H H H CH(CO2H)CH2 bond 415[M − CO2H]− 13 D105 H 4-I HH H C(═O)—C(Me)2 bond 459 15 D106 H 3-NO2 H H H (C═O)—C(Me)2 bond 378 15D107 H 3-NO2 H H H C(═O)—O— bond 352 15 D108 H 4-I H H H C(═O)—O— bond433 15 D109 H 3-NO2 H H H CH(CH2OH)CH2 bond 366 21 Isomer 1 D110 H 3-NO2H H H CH(CH2OH)CH2 bond 366 21 Isomer 2 D111 H 4-I H H H CH(CH2OH)CH2bond 447 21 Isomer 1 D112 H 3,5-di-F H H H CH(CH2OH)CH2 bond 341 21Isomer 1 D113 H 4-I H H H CH(CH2OH)CH2 bond 447 21 Isomer 2 D114 H3,5-di-F H H H CH(CH2OH)CH2 bond 341 21 Isomer 2

[0641] TABLE E Encompassing compounds of general formula (XXX-6),wherein group R² of formula (I) is a (3-heterocyclyl) moiety (XXX-7),optionally substituted by one or more substituents R¹³ and group R³ offormula (I) is a phenyl ring, optionally substituted by one or moresubstituents R¹¹ and substituents R, R¹, R¹¹ and R¹³ are listed in TableE. (XXX-6)

(XXX-7)

[M + H]⁺ Observed; For Procedure (Unless [M]⁻ or See Example [M − H]⁻are Example No. R R¹ R¹¹ R¹³ A Indicated) No. E1 H H 3-Br4,5-[(—CH═CH—)2] N(Me) 396/398 4 E2 H H 4-Me 4,5-[(—CH═CH—)2] N(Me) 3324 E3 H H 4-SMe 4,5-[(—CH═CH—)2] N(Me) 364 4 E4 H H 3-Br-4-Me4,5-[(—CH═CH—)2] O 397/399 4 E5 H H 3-Br-4-Me H S 363/365 4 E6 H H 3-ClH S 303/305[M − H]− 1 E7 H H 3,4-[S—CH═N] 4,5-[(—CH═CH—)2] N(Me) 375 4E8 H H 3-OPh 4,5-[(—CH═CH—)2] N(Me) 410 4 E9 H H 3,4-[(CH2)3]4,5-[(—CH═CH—)2] N(Me) 358 4 E10 H H 3-SMe H S 315[M − H]− 1 E11 H H4-Me H S 283[M − H]− 1 E12 H H H H S 269[M − H]− 1 E13 H H 3-OPh H S361[M − H]− 1 E14 H H 3,4-[(CH2)3] H S 309[M − H]− 1 E15 H H 3-Br H S347/349[M − H]− 1 E16 H H 4-SMe H S 315[M − H]− 1 E17 H H 3,5-di-Br-4-OHH S 441/443/445[M − H]− 1 E18 H H 3-Cl 4,5-[(—CH═CH—)2] S 355/357 1 E19H H 3,5-di-Cl-4-OH H S 353/355/357[M − H]− 1 E20 H H 3,5-di-Cl-4-OH4,5-[(—CH═CH—)2] S 405/407/409 13 E21 H H 3-CO2H-4-Cl H S 349/341 1 E22H H 3,4-[OCH2O] H S 315 1 E23 H H 3-Cl-4-OH H S 319/321[M − H]− 1 E24 HH 3,5-di-F H S 307 1 E25 H H 3-CH2OH H S 299[M − H]− 1 E26 H H 3-OH H S287 1 E27 H H 3,4-[OCH2O] 4,5-[(—CH═CH—)2] S 365 1 E28 H H 3-Cl-4-OH4,5-[(—CH═CH—)2] S 371/373 1 E29 H H 3-OH 4,5-[(—CH═CH—)2] S 337 1 E30 HH 4-CH2SO2NHMe H S 378 1

[0642] TABLE F Encompassing compounds of general formula (XXX-8),wherein group R² of formula (I) is a moiety of formula (XXX-9),optionally substituted by substituents R¹⁴ and R¹⁵ and group R³ offormula (I) is a phenyl ring, optionally substituted by one or moresubstituents R¹¹ and substituents R, R¹, R¹¹, R¹⁴ and R¹⁵ are listed inTable F. (XXX-8)

(XXX-9)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example No. R R¹ R¹¹R¹⁴ R¹⁵ [M − H]⁻ are Indicated) See Example No. F1 H H 3,4-[(CH2)3] H Me360[M − H]− 7 F2 H H 3,4-[(CH2)3] H NH[3-F—Ph] 456[M]− 8 F3 H H3,4-[(CH2)3] H NH(CH2)2Ph 467 8 F4 H H 3,4-[(CH2)3] H NH[Cyclohexyl]443[M − H]− 8 F5 H H 3,4-[(CH2)3] H NHCH2CH═CH2 403 8 F6 H H3,4-[(CH2)3] H Ph 422[M − H]− 9 F7 H H 3,4-[(CH2)3] H CH2Ph 436[M − H]−9 F8 H H 3,4-[(CH2)3] H trans-CH═CHPh 450 9 F9 H H 3,4-[(CH2)3] H n-Pr390 9 F10 H H 3,4-[(CH2)3] H NHEt 389[M − H]− 8 F11 H H 3,4-[(CH2)3] HNH[3-OMe—Ph] 469 8

[0643] TABLE G Encompassing compounds of general formula (XXX-10),wherein group R² of formula (I) is a phenyl ring, optionally substitutedby one or more substituents R¹⁰ and group R³ of formula (I) is a moietyof formula (XXX-11), optionally substituted by one or more substituentsR¹⁶ and R¹⁷ and substituents R, R¹, R¹⁰, W, R¹⁶ and R¹⁷ are listed inTable G. The position of substituent R¹⁶ is indicated by the locants 2or 3 in structure (XXX-10). (XXX-10)

(XXX-11)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example No. R R¹ R¹⁰ WR¹⁶ R¹⁷ [M − H]⁻ are Indicated) See Example No. G1 H H 2-OMe S 3-CO2H2-CO2H 491 1 G2 H H 4-Cl S H 3-CO2H 449/451[M − H]− 1 G3 H H 4-Cl S3-CO2Et 2-CO2Et 550/552[M]− 1 G4 H H 4-Cl S 3-CO2Me 4-Cl 497/499/501[M −H]− 1 G5 H H 4-Cl S 3-CO2H 2-CONHMe 508/510 1 G6 H H 4-Cl S H 4-NO2450/45[M − H]− 1 G7 H H 4-Cl O H 4-Cl 425/427/429 1 G8 H H 4-Cl S H2-CO2H 451/453 1 G9 H H 4-Cl S 3-CO2H H 449/451[M − H]− 1 G10 H H 4-OMeS 3-CO2H 2-CO2H 489[M − H]− 1 G11 H H 2-Cl S 3-CO2H 2-CO2H 493[M − H]− 1G12 H H 4-Cl S 3-CO2H 3-CO2H 495/497 1 G13 H H 2,3-di-F S H 3-CO2H 453 1G14 H H 2,3-di-F S 3-CONHMe 2-CONHMe 523 1 G15 H H 2,3-di-F S 3-CO2H2-CO2Et 523[M − H]− 1 G16 H H 2,3-di-F S H 4-CO2H 451[M − H]− 1 G17 H H2,3-di-F S 3-CO2Et 4-CO2H 525 1

[0644] TABLE H Encompassing compounds of general formula (XXX-12),wherein group R² of formula (I) is a (2-heterocyclyl) moiety (XXX-13),optionally substituted by one or more substituents R¹⁸ and group R³ offormula (I) is a phenyl ring, optionally substituted by one or moresubstituents R^(11 and substituents, R, R) ¹, R¹¹ and R¹⁸ are listed inTable H. (XXX-12)

(XXX-13)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example No. R R¹ R¹¹R¹⁸ A [M − H]⁻ are Indicated) See Example No. H1 H H 3-Cl H S 305/307 1H2 H H 3-Cl 3-Me-4,5-[(—CH═CH—)2] S 369/371 1 H3 H H 3,5-di-Cl-4-OH H S355/357/359 1 H4 H H 3,5-di-Cl-4-OH 3-Me-4,5-[(—CH═CH—)2] S 419/421/42313

[0645] TABLE I Encompassing compounds of general formula (XXX-14),wherein the moiety NR¹R³ of formula (I) is represented by a generalsubstituent R¹⁹ and substituents R, R² and R¹⁹ are listed in Table I.(XXX-14)

[M + H]⁺ Observed; (Unless [M]⁻ or For Procedure Example No. R R² R¹⁹ [M− H]⁻ are Indicated) See Example No. I1 H 3-Thienyl 1-Indolinyl 297 1 I2H 2-Thienyl 1-Indolinyl 297 1 I3 H 4-Cl—Ph (3-Amino-1-pyridinium 301/30319 chloride) I4 H 2-Thienyl 2-Me-Indolin-1-yl 311 1 I5 H 3-Thienyl2-Me-Indolin-1-yl 311 1 16 H 2,4-di-Cl—Ph [1,3,3-Trimethyl-6-aza-393/395/397 1 bicyclo[3,2,1]octan-6-yl] I7 H 2,4-di-Cl—Ph[1-Phenyl-1,3,8-triaza- 471/473/475 1 spiro-[4,5]-de- can-4-one-8-yl]

1. A method for the treatment of conditions associated with a need forinhibition of GSK-3, such as diabetes, dementias such as Alzheimer'sdisease and manic depression which method comprises the administrationof a pharmaceutically effective, non-toxic amount of a compound offormula (I):

or a pharmaceutically acceptable derivative thereof, wherein: R ishydrogen, alkyl, aryl, or aralkyl; R¹ is hydrogen, alkyl, aralkyl,hydroxyalkyl or alkoxyalkyl; R² is substituted or unsubstituted aryl orsubstituted or unsubstituted heterocyclyl; R³ is hydrogen, substitutedor unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkylwherein the aryl moiety is substituted or unsubstituted; or, R¹ and R³together with the nitrogen to which they are attached form a single orfused, optionally substituted, saturated or unsaturated heterocylicring; to a human or non-human mammal in need thereof.
 2. A compound offormula (IB),

or a derivative thereof, wherein: R is hydrogen, alkyl, aryl, oraralkyl; R¹ is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; R²is substituted or unsubstituted aryl or substituted or unsubstitutedheterocyclyl; R³ is hydrogen, substituted or unsubstituted alkyl,cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heterocyclyl or aralkyl wherein the aryl moiety issubstituted or unsubstituted; or, R¹ and R³ together with the nitrogento which they are attached form a single or fused, optionallysubstituted, saturated or unsaturated heterocylic ring; with the provisothat formula (IB) does not include the compounds contained in List B. 3.A compound according to claim 2 of formula (IC′)

wherein; R and R¹ are as defined in relation to formula (I) in claim 1;R¹⁰ represents hydrogen or one or more substituents, suitably up tothree, selected from the list consisting of: alkoxycarbonyl,alkoxyalkyl, perfluoroalkyl, perfluoroalkylS—, perfluoroalkylO—,phenyl(di-C₁₋₆alkoxy)C—, benzoyl, C₁₋₆alkylSO₂—, —[(CH═CH)₂]—, phenyl,nitro, —OCH₂O—, benzyloxy, phenoxy, halo, hydroxy, alkyl, alkoxy, amino,mono- or di-alkyl amino or thioalkyl; R¹¹ represents hydrogen or one ormore substituents, suitably up to three, selected from the listconsisting of: substituted or unsubstituted C₁₋₆alkyl, phenyl, benzyl,substituted or unsubstituted C₁₋₆alkylS—, halo, hydroxy, substituted orunsubstituted C₁₋₆alkoxy, substituted or unsubstituted phenoxy, indolyl,naphthyl, carboxy, C₁₋₆alkoxycarbonyl, benzyloxy, phenoxy,pentafluorophenoxy, nitro, substituted or unsubstituted carbamoyl,substituted or unsubstituted C₁₋₆alkylcarbonyl, benzoyl, cyano,perfluoroC₁₋₆alkylSO₂—, C₁₋₆alkylNHSO₂—, oxazolyl, substituted orunsubstituted phenylS—, C₁₋₆alkylpiperazinyl-,C₁₋₆alkylcarbonylpiperazinyl-, 1,2,3-thiadiazolyl, pyrimidin-2-yloxy,N-[pyrimidin-2-yl]-N-methylamino, phenylamino, C₁₋₆alkylsulphonylamino,N-morpholinylcarbonyl, cyclohexyl, adamantyl, trityl, substituted orunsubstituted C₁₋₆alkenyl, perfluoroC₁₋₆alkyl, perfluoroC₁₋₆alkoxy,perfluoroC₁₋₆alkylS—, aminosulphonyl, morpholino, (diC₁₋₆alkyl)amino,C₁₋₆alkylCONH—, (diC₁₋₆alkoxy)phenyl(CH₂)_(n)NHC(O)CH(phenyl)S— where nis 1 to 6, and C₁₋₆alkylCON(C₁₋₆alkyl)-, thiazolidinedionylC₁₋₆alkyl,phenylCH(OH)—, substituted or unsubstituted piperazinylC₁₋₆alkoxy,substituted or unsubstituted benzoylamino; or —(CH₂)_(x)—, —SCH═N—,—SC(C₁₋₆alkyl)═N—, —OCF₂O—, —[CH═CHC(O)O]—, —[N═CH—CH═CH]—, —CH═N—NH—,—CH═CH—NH—, —OC(NHC₁₋₆alkyl)═N—, —OC(O)NH—, —C(O)NMeC(O)—, —C(O)NHC(O)—,—(CH₂)_(x)C(O)—, —N═N—NH—, —N═C(C₁₋₆alkyl)O—, —O(CH₂)_(x)O—,—(CH₂)_(x)SO₂(CH₂)_(y)—, and —N(C₁₋₆alkylcarbonyl)(CH₂)_(x)—, where xand y are independently 1 to 4; with the proviso that (IC′) does notinclude: 3-phenylamino-4-phenyl-1H-pyrrole-2,5-dione;1-(4-methylphenyl)-3-[(4-methylphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;3-(4-methylphenyl)-1-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione;1,3-bis(4-methylphenyl)-4-[(4-methylphenyl)amino]-1H-yrrole-2,5-dione,or; 3-(4-nitrophenyl)-1-phenyl-4-phenylamino-1H-pyrrole-2,5dione.
 4. Acompound according to claim 3 wherein R and R¹ each represent hydrogen,and; R¹⁰ and R¹¹ are defined as follows: when R¹⁰ is 4-Cl, then R¹¹ is3-Cl, 3-Br, or 4-CH₂SO₂NHMe; when R¹⁰ is 2-OMe, then R¹¹ is 4-OMe or3,5-di-F; when R¹⁰ is 2-F, then R¹¹ is 3,5-di-F; when R¹⁰ is 3-F, thenR¹¹ is 4-(CH₂)₃CO₂H; when R¹⁰ is 2,3-di-F—Ph, then R¹¹ is 3,5-di-F.
 5. Acompound according to claim 2 of formula (ID′)

wherein R and R¹ are as defined in relation to formula (I) in claim 1;R^(2′) is phenyl, substituted phenyl or indolyl; R^(3′) is hydrogen,alkyl, cycloalkyl, phenyl, substituted phenyl, C₁₋₆ alkylphenyl whereinthe phenyl group is optionally substituted, alkoxyalkyl, substituted orunsubstituted heterocyclyl, with the proviso that formula (ID′) does notinclude the compounds contained in List D′.
 6. A compound according toclaim 2 of formula (IE′)

wherein R is as defined in relation to formula (I) in claim 1; R^(10′)represents hydrogen or one or more, suitably up to three, substituentsselected from the list consisting of: alkoxy, halo, and nitro; P′—Q′represents —CH₂)_(a)O(CH₂)_(b)—, —CH₂)_(a)S(CH₂)_(b)—, —(CH₂)_(c)—,—(CH₂)_(d)CH(G)(CH₂)_(e)—, —(CH₂)_(a)N(ZZ)(CH₂)_(b)—, where a, b, d, ande are independently 1 to 4, c is 1 to 6, ZZ is hydrogen, alkyl, aryl, oralkylcarbonyl, and G is alkyl, amido, hydroxyalkyl, aralkyl, or hydroxy,with the proviso that (IE′) does not include:3-phenyl-4-piperidin-1-yl-pyrrole-2,5-dione;3-(4-methylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;3-(4-ethylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;3-(4-chlorophenyl)-4-(4-methyl-piperazin-1-yl)-pyrrole-2,5-dione;3-(4-methylphenyl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;1-methyl-3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;1-ethyl-3-phenyl-4-(4-chlorophenylpiperazino)-pyrrole-2,5-dione;1-allyl-3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione, and;1,3-diphenyl-4-piperidino-pyrrole-2,5-dione.
 7. A compound according toclaim 2 of formula (IF)

wherein R is as defined in relation to formula (I) in claim 1; R10″ isone or more, suitably up to three, substituents selected from the listconsisting of perfluoroalkyl, halo, nitro, alkoxy, arylcarbonyl, alkyl;Z is a bond or an alkylene chain; —X—Y— is —CH═N, —(CH₂)_(t)—,—(CH₂)_(u)CH(U)—, —(U)CH(CH₂)_(u)—, —CH═CH—, —(CH₂)_(v)C(alkyl)₂- ,—C(O)C(alkyl)₂- , —C(O)O—, where t, u, and v are independently 1 to 4,and U is alkyl, carboxy, alkoxycarbonyl, hydroxyalkyl, and amido;R^(12a′), R^(12b′), and R^(12c′) are each independently hydrogen, nitro,alkoxy, 4-ethylpiperazin-1-yl, 4-BOC-piperazin-1-yl,4-methyl-piperazin-1-yl, 4-methyl-piperazin-1-yl, halo, alkyl,piperazin-1-yl, perfluoroalkyl, and alkylsulphonylamino.
 8. A compoundaccording to claim 2 of formula (IG)

wherein R and R¹ are as defined in relation to formula (I) in claim 1; Ais N(alkyl), oxygen, or sulphur. Examples of A are N(methyl), oxygen,and sulphur. Preferably, A is sulphur. R^(11″) is one or more, suitablyup to three, substituents selected from the group consisting ofhydrogen, halo, alkyl, alkylthio, —S—CH═N—, phenoxy, —(CH₂)_(w)—,hydroxy, carboxy, —O(CH₂)_(x)O—, hydroxyalkyl, andalkylaminosulphonylalkyl, where w and x are independently 1 to
 4. 9. Acompound according to claim 2 of formula (IH)

wherein R and R¹ are as defined in relation to formula (I) in claim 1;R^(11′″) is —[(CH₂)_(aa)]—, where aa is 1 to 4; R^(14′) is hydrogen;R^(15′) is alkyl, unsubstituted or substituted phenylamino,unsubstituted or substituted phenylalkylamino, cyclohexylamino,alkenylamino, phenyl, benzyl, styryl, or alkylamino.
 10. A compoundaccording to claim 2 of formula (IJ)

wherein R and R¹ are as defined in relation to formula (I) in claim 1;R^(10″′) represents one or more, suitably up to three, substituentsindependently selected from alkoxy or halo; R^(16′) represents one ormore, suitably up to three, substituents independently selected fromhydrogen, carboxy, alkoxycarbonyl, or alkylaminocarbonyl; R^(17′)represents one or more, suitably up to three, substituents independentlyselected from carboxy, alkoxycarbonyl, halo, alkylaminocarbonyl, nitro,or hydrogen; W is sulphur, oxygen, or substituted or unsubstituted NH.11. A compound according to claim 2 of formula (IK)

wherein R and R¹ are as defined in relation to formula (I) in claim 1;R^(11″″) represents one or more, suitably up to three, substituentsindependently selected from halo and hydroxy; R^(18′) represents one ormore, suitably up to three, substituents independently selected fromhydrogen, alkyl, and —(CH═CH)₂—; A is sulphur.
 12. A compound accordingto claim 2 of formula (IL′)

wherein R is as defined in relation to formula (I) in claim 1; R^(2′″)is unsubstituted or substituted heterocyclyl or unsubstituted orsubstituted aryl; R^(19′) is unsubstituted or substituted heterocyclyl,or a quatemised salt thereof, with the proviso that formula (IL′) doesnot include the compounds contained in List L′.
 13. A process for thepreparation of a compound of the invention which process comprisesreaction of a compound of formula (II):

wherein R and R² are as defined in formula (I) in claim 1 and L is aleaving group, with a compound of formula (III):

wherein R¹ and R³ are as defined in formula (I) in claim 1; andthereafter, if required, carrying out one or more of the followingoptional steps: (i) converting a compound of formula (I) to a furthercompound of formula (I); (ii) removing any necessary protecting group;(iii) preparing an appropriate derivative of the compound so formed. 14.A compound of formula (I) according to claim 1 for use in conditionsassociated with a need for inhibition of glycogen synthase kinase-3. 15.Use of a compound of formula (I) according to claim 1 for themanufacture of a medicament for the treatment of conditions associatedwith a need for the inhibition of glycogen synthase kinase-3.
 16. Acompound of formula (IA)

wherein R is hydrogen, alkyl, aryl, or aralkyl; R¹ is hydrogen, alkyl,aralkyl, hydroxyalkyl or alkoxyalkyl; R² is substituted or unsubstitutedaryl or substituted or unsubstituted heterocyclyl; R³ is hydrogen,substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl oraralkyl wherein the aryl moiety is substituted or unsubstituted; or, R¹and R³ together with the nitrogen to which they are attached form asingle or fused, optionally substituted, saturated or unsaturatedheterocylic ring; or a pharmaceutically acceptable derivative thereof,for use as an active therapeutic substance, with the proviso thatformula (IA) does not include the compounds contained in List A.
 17. Apharmaceutical composition which comprises a compound of formula (IA)

wherein R is hydrogen, alkyl, aryl, or aralkyl; R¹ is hydrogen, alkyl,aralkyl, hydroxyalkyl or alkoxyalkyl; R² is substituted or unsubstitutedaryl or substituted or unsubstituted heterocyclyl; R³ is hydrogen,substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl oraralkyl wherein the aryl moiety is substituted or unsubstituted; or, R¹and R³ together with the nitrogen to which they are attached form asingle or fused, optionally substituted, saturated or unsaturatedheterocylic ring; or a pharmaceutically acceptable derivative thereof,and a pharmaceutically acceptable carrier, with the proviso that formula(IA) does not include the compounds contained in List A.
 18. A methodfor the treatment and/or prophylaxis of mood disorders in a mammal,which method comprises the administration of a pharmaceuticallyacceptable amount of a GSK-3 inhibitor.
 19. A method for the treatmentand/or prophylaxis of neurotraumatic diseases in a mammal, which methodcomprises the administration of a pharmaceutically acceptable amount ofa GSK-3 inhibitor.
 20. A method for the treatment and/or prophylaxis ofcancer, in a mammal, which method comprises the administration of apharmaceutically acceptable amount of a GSK-3 inhibitor.
 21. A methodfor the treatment and/or prophylaxis of hair-loss, in a mammal, whichmethod comprises the administration of a pharmaceutically acceptableamount of a GSK-3 inhibitor.
 22. Use of a GSK-3 inhibitor for themanufacture of a medicament for the treatment and/or prophylaxis of mooddisorders, schizophrenia, neurotraumatic diseases, cancer or hair-loss.23. A compound of formula (I)

or a derivative thereof, wherein: R is hydrogen, alkyl, aryl, oraralkyl; R¹ is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; R²is substituted or unsubstituted aryl or substituted or unsubstitutedheterocyclyl; R³ is hydrogen, substituted or unsubstituted alkyl,cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heterocyclyl or aralkyl wherein the aryl moiety issubstituted or unsubstituted: or, R¹ and R³ together with the nitrogento which they are attached form a single or fused, optionallysubstituted, saturated or unsaturated heterocylic ring; with the provisothat the compounds of formula (ID)

wherein R and R¹ are as defined in relation to formula (I); R^(2′) isphenyl, substituted phenyl or indolyl; R^(3′) is hydrogen, alkyl,cycloalkyl, phenyl, substituted phenyl, C₁₋₆ alkylphenyl wherein thephenyl group is optionally substituted, alkoxyalkyl, substituted orunsubstituted heterocyclyl; are excluded.